Bichromonyl compounds

ABSTRACT

Compounds of the formula   IN WHICH P to T1 are hydrogen, alkyl, alkoxy, alkenyl, alkenyloxy, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkenyloxy, amino, substituted amino aminoalkoxy, substituted aminoalkoxy, nitro, halo, hydroxy, or benzyloxy; the R1 groups are hydrogen, substituted or unsubstituted alkyl, alkoxy or aryl; and X is a carbon - carbon bond or a single atom, which may be substituted, through which the chromone nuclei are linked, and pharmaceutically acceptable derivatives thereof, are indicated for use in the treatment of &#39;&#39;extrinsic&#39;&#39; allergic asthma.

United States Patent Cairns et al.

[ 1 June 27,1972

BICHROMONYL COMPOUNDS inventors: Hugh Cairns; Peter Bennett Johnson,both of Loughborough, England Assignee: Fisons Pharmaceuticals Limited,

Loughborough, England Filed: Oct. 28, 1969 Appl. No.: 871,972

Foreign Application Priority Data Oct. 30, i968 Great Britain..5l,42l/68 U.S. Cl ..260/45.2, 260/345.5, 424/283,

260/296 B, 260/297 B, 260 2948 0, 260/295 F, 260/293.58, 260/613 R,260/609 R, 260/576,

260/6I9 R. 260/620. 260/296 AE,260/297 R,

260/5 l4 R. 260/469. 260/470. 260/47 R. 260/473 R. 260/473 5, 260/475 R.260/475 $0 161. CI. ..C07d 7/4 Field 6: Search ..260/345.2, 345.5, 296B, 297 B, 260/294.8 o, 295 F, 293.58

Reierences Cited UNITED STATES PATENTS Fitzmaurice et a1. ..260/345.2

3,519,652 7/1970 Fitzmaurice etal. ..-.....260/345.2

Primary Examiner-John M. Ford Attorney-Wenderoth, Lind & Ponack 57ABSTRACT Compounds of the formula P Pr l l 0 2 v 6 201 ll (H O X \0 )HQ, Q1 T1 in which P to T, are hydrogen, aikyl, alkoxy, alkenyl, al;kenyioxy, substituted alkyl, substituted alkoxy, substituted a]; kenyl,substituted alkenyloxy, amino, substituted amino aminoalkoxy,substituted aminoalkoxy, nitro, halo, hydroxy, or benzyloxy; the Rgroups are hydrogen, substitutedor un; substituted alkyl, alkoxy oraryl; and X is a carbon carbon bond or a single atom, which may besubstituted, through which the chromone nuclei are linked, andpharmaceutically acceptable derivatives thereof, are indicated for usein the treatment of extrinsic allergic asthma.

Q4 Claims, No Drawings BICHROMONYL COMPOUNDS The present inventionrelates to novel compounds, their preparation and use.

The invention provides as novel compounds, compounds of the formula QO/CO OH I P P1 f l X H O O C Q Q T and functional derivatives thereofwherein P Q, T, P,, Q, and

T, may be the same or different and each may be selected from hydrogenand substituents other than hydrogen; the R groups may be the same ordifferent and each is selected from hydrogen, a substituted orunsubstituted alkyl or alkoxy group containing from one to ten carbonatoms and a substituted or unsubstituted aryl group; and X is a carbonto carbon bond or a single atom through which the chromone nuclei arelinked, which single atom may carry substituents which do not form partof the linkage itself between the two chromone nuclei.

The X atom may be an oxygen or sulphur atom, may be a substitutedsulphur or nitrogen atom or may be a methylene group or a substitutedmethylene group. The substituents may be linked to the linkage atom bysingle bonds, as with an hydroxymethylene linkage, or by double bonds,as with a carbonyl group linkage. Specific examples of such substitutedatoms are the group -SO, -SO,,,

NH and NR" groups [where R is an alkyl, alkenyl, alkoxy, aralkyl, aryl,acyl, hydroxy, carboxy or a carbocyclic or heterocyclic ring or suchgroups or rings carrying further substituents such as hydroxy, halogen,alkyl, alkoxy or aryl group] such as an Where X- is a substitutedmethylene group, it may have the formula wherein each R may be the sameor different and is an hydrogen; an hydroxy; an halogen; an alkyl,alkenyl or alkynyl group which may or may not have any carbon atomtherein replaced by a group such as an oxygen, sulphur or nitrogen atomor a carbonyl group or an amide or ester linkage, which groups may carryfurther substituents such as halogen, hydroxy, carboxy or alkoxy groups;a carboxylic acid group (including salts, esters and amides thereof); anaryl, aralkyl, aryloxy or aralkoxy group which may carry any of thesubstituents listed above; and an heterocyclic or carbocyclic ring whichmay carry any of the substituents listed above. The methylene group mayalso have substituents linked thereto by double bonds as is the casewith the groups X- atom or substituted atom is Maze R being an alkylgroup, notably a lower alkyl group such as a methyl group, ethyl, propylor pentyl group.

The term lower is used herein to mean a group containing from one to sixcarbon atoms.

As indicated above, the X- linkage may be merely a carbon to carbon bondbetween the chromone nuclei and this form of linkage is particularlypreferred.

The linking bond or atom X may link the two chromone nuclei in any ofthe free positions thereon, i.e. in the 5, 6, 7 or 8 positions. It isusually preferred that the linkage be between the same positions on thechromone nuclei, e.g. between the 6 and 6 or the 7 and 7 positions.

The P, Q, T, P,, Q, and T, substituents need not all be the same and maybe selected from a number of groups. Examples of suitable groups includealkyl groups, notably those containing from one to eight carbon atoms,which may be straight or branched (such as methyl, ethyl or isopropylgroups) and which may carry one or more substituents, such as hydroxy,alkoxy or halo groups, e.g. an hydroxymethyl, hydroxy propyl,ethoxyethyl, or chloromethyl group; alkoxy groups corresponding to suchalkyl groups, e.g. an isopropoxy, an hydroxypropoxy group or anethoxyethoxy group; alkenyl or alkenyloxy groups corresponding to suchalkyl or alkoxy groups; amino groups which may carry substituents, suchas a monoor di-lower alkyl amino group; aminoalkoxy groups which maycarry substituents such as a di-lower alkylamino lower alkoxy group; anitro group; an hydroxy group; or an halogen atom. Specific examples ofsuitable groups are chloro, bromo, iodo, hydroxy, acetoxy, nitro,methyl, ethyl, propyl, butyl, tert. butyl, allyl, l-methylallyl,prop-l-enyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, but-3-enoxy,acetyl, hydroxymethyl, ethoxymethyl, chloromethyl, 2-chloroethoxy,2-iodoethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy,2,3-dihydroxypropoxy, 2-hydroxybutoxy, 3-methylbutoxy, 2-ethoxyethoxy,3methoxy-2hydroxypropoxy, 3-butoxy-2-hydroxypropoxy, diethylaminoethoxy,aminoethylamino and acetylamino. It is, however, preferred that-P, Q, T,P,, Q, and T, all be hydrogen.

R may have any of the values specified above, particularly hydrogen; aloweralkyl group, such as a methyl, ethyl, propyl, or pentyl group; alower alkoxy group corresponding to such alkyl groups; or an aryl groupsuch as a phenyl group. It is preferred that both R groups be hydrogen.

It will be appreciated that certain of the above values of P, v

Q, T, P,, Q,, T and R may include groups which could be detrimentallyaffected by the reactants and/or reactant conditions used to introduceother groups into the molecule. In such cases the susceptible group maybe blocked or shielded, for example by alkylation, acetylation orbenzylation for all or part of the processes during which the compoundsof formula I are prepared; or by the blocking of the reactive site by aremovable group, such as a cyano or nitro group, which may be removed atthe end of a preparative process to permit introduction of the desiredgroup or hydrogen atom in a final stage. The values for the P, Q, T, P,,Q, and T, and R groups given herein are therefore to be construed toinclude, where permissible, a shielded or blocked precursor orderivative of the desired value for the substituent. The presence of ablocking group on the benzene ring may have the added advantages that itmay assist linkage of that ring to another and may also ensure that theformation of the desired COCR'=C(COOH)-O- chain occurs between thecorrect positions on the benzene ring and not on others.

Particularlypreferred compounds of the present invention are those ofthe general formula and functional derivatives thereof (notably thesodium and ammonium salts; alkyl, dialkylamino-alkyl and piperidinoalkylesters where the alkyl groups have from one to six carbon.

atoms, e.g. ethyl groups; and amides derived from ammonia, aminoacidssuch as glycine and dialkylaminoalkyl amines, e.g.diethylaminoethylmine) wherein X is a carbon to carbon bond, a

or substituted group, an -S, SO-, --SO or group linking the 6 and 6' or7 and 7 positions of the two chromone nuclei; and P, Q, T, P Q and T maybe the same or different and each is selected from hydrogen, hydroxy,halogen and lower alkyl or alkoxy groups, which groups may carry one ormore hydroxyl, alkoxy or dialkylamino groups as substituents. It isespecially preferred that X be a carbon to carbon bond or an S- atomlinking the 6 and 6 positions of the chromone nuclei and that P-T areall hydrogen.

Functional derivatives of the compounds according to the inventioninclude salts, notably water-soluble salts; esters and amides of one ormore of the carboxylic acid functions present and derivatives of anyother functional groups present.

Salts of the compounds which may be mentioned are salts withphysiologically acceptable cations, for example, ammonium salts; metalsalts, such'as alkali-metal salts (e.g. sodium potassium and lithiumsalts) and alkaline-earth metal salts (e.g. magnesium and calciumsalts); and salts with organic bases, e.g. amine salts derived frommono-, dior tri-lower alkyl or lower alkanolamines, (such astriethanolamine or triethylamine) and salts with heterocyclic aminessuchas piperidine or pyridine.

Esters which may be mentioned include simple alkyl esters derived fromalcohols containing from one to ten carbon atoms (e.g. a methyl,ethyl,propyl, or pentyl ester) and alkylaminoalkyl esters, such as those ofthe general formula COO-R"NR"'R"" wherein R" is a branched or straightalkylene chain (e.g. one containing from one to four carbon atoms suchas a methylene, ethylene, propylene, isopropylene or tert. butylenegroup); and R and R"" may be the same or different and each is selectedfrom hydrogen or an alkyl group. (e.g. a lower alkyl group such as amethyl, ethyl, propyl or butyl group) or together with the nitrogen atomform an heterocyclic ring such as a piperidine or morpholine ring.Examples of such basic esters are diethylaminoethyl and piperidinoethylesters. The basic esters may be in the form of an acid addition saltthereof with a physiologically acceptable acid, e.g. hydrochloric acid.

Amides which may be mentioned include simple amides derived from ammoniaor primary or secondary aliphatic or aromatic amines, such as monoordi-lower alkyl amines (for example diethylamine), aniline or amono-alkylaniline such as methyl aniline; and more complex amidesderived from amino acids such as glycine, i.e. amides of the formula--CONR- R" COOl-l, or salts and esters thereof, and from monoorbis-(dialkylamino-alkyl) amines, i.e. amides of the formula CONRR"R"'R""wherein R is hydrogen or an alkyl group (e.g. a lower alkyl group suchas a methyl, ethyl, propyl or butyl group) andR", R and R"" have thevalues given above. The amides may exist in the form of an acid saltthereof, e. g. an hydrochloride.

Other functional groups in the molecule may be in the form ofderivatives thereof. Thus, acidic groups other than the 2- carboxylicacid group may be in the form of a salt, ester or amide as describedabove, or may be in the form of an ureide,

or hydrazide. Hydroxyl groups may be in the form of an acylated orbenzylated derivative thereof, an ester or acetal group or in the formof an alkali-metal derivative thereof. Carbonyl groups may be in'theform of an oxime. Amino groups may be in the form of a salt thereof witha pharmaceutically acceptable acid, such as hydrochloric, citric,succinic or oxalic acid, or in the form of a quaternary ammonium salt.

The new compounds of the invention have been shown to inhibit therelease of toxic products which arise from the combination of certaintypes of antibody and specific antigen, e. g. the combination ofreaginic antibody with specific antigen. In man, both subjective andobjective changes which result from the inhalation of specific antigenby sensitized subjects may be markedly inhibited by administration ofthe new compounds. Thus, the new compounds are indicated for use in thetreatment of extrinsic allergic asthma. Thenew compounds may also be ofvalue in the treatment of so-called intrinsic asthma (in which nosensitivity to extrinsic antigen can be demonstrated) and in thetreatment of other conditions in which antigenantibody reactions areresponsible for disease, for example, hay fever, urticaria andauto-immune diseases.

According to a further feature of the invention, therefore, there isprovided a pharmaceutical composition comprising a compound of formulaI, or a derivative thereof, preferably in the form of a salt, inassociation with a pharmaceutically acceptable carrier or diluent. Thereis also provided a process for the manufacture of such a pharmaceuticalcomposition which comprises mixing a compound of formula I with acarrier or diluent.

The nature of the composition and the pharmaceutically acceptablecarrier or diluent will, of course, depend upon the desired mode ofadministration, which may be for example, orally; by inhalation;parenterally; or by topical application.

The composition may be formulated in the conventional manner with thecustomary ingredients. For example the compositions may be put up asaqueous solutions or suspensions, as powders or in tablet, cream, lotionor syrup form.

The compositions of the invention generally comprise a minor proportionof the compound of formula I and a major proportion of carrier ordiluent. Thus, for example, aqueous solutions for administration bymeans of a conventional nebulizer may contain up to about 10 percent byweight of the active ingredient in sterile water; and compositions fordispensing from a pressurized container comprising suspensions orsolutions in liquefied propellants will contain, for example, aboutO.2-5 percent by weight of the active ingredient.

The compounds of formula I are preferably administered by inhalation,notably in the treatment of allergic asthma. For such use, the compoundsof formula I, preferably in the form of a salt such as the sodium salt,are dissolved or suspended in water and may be applied by means of aconventional nebulizer. However the administration of medicaments bymeans of a pressurized dispensing container, i.e. an aerosol dispenser,is an alternative to nebulizer administration. For administration from aaerosol dispenser, the medicament is dissolved or suspended in aliquefied propellant medium. The propellants for presentuse may be anyof those which are conventionally used in formulations for dispensingfrom pressurized containers. For example they may be of the halogenatedhydrocarbon type such as fluoroor fiuorohalohydrocabons, e.g.trichloromonofluoromethane, dichlorodifluoromethane,dichlorotetrafluoroethane, monochlorotrifluoromethane,monochlorodifluoromethane and mixtures of any of these together or withother propellants. Typical suitable propellants are those disclosed in,for example, US. Pat. No. 2868691 and sold under the trade name ofFreon. It is preferred that the propellant should be of low toxicity,especially where the composition is to be ingested, e. g. inhaled, bythe user. It is I therefore preferred to use difluorodichloromethane,dichlorotetrafluoroethane or mixtures thereof. Where the medicament isnot soluble in the propellant, it may be necessary to add asurface-active agent to the composition in order to suspend themedicament in the propellant medium, and such surface-active agents maybe any of those commonly used for this purpose, such as nonionicsurface-active agents. However, we prefer to use the anionic dialkylsulphosuccinate or alkyl benzene sulphonate surface-active agents. Theuse of such surface-active agents and the advantages which stemtherefrom are more fully described in British Pat. Spec. No. 1063512.

The compositions of the invention may also be administered in the formof powders by means of an insufllator device, such as that described inBritish Pat. Spec. No. 1122284. In order to improve the properties ofthe powder, it may be desired to modify the surface characteristics ofthe powder particles, for example, by coating them with apharmaceutically acceptable material such as sodium stearate. Inaddition, fine particle sized powders of the active ingredients may bemixed with a coarser diluent material, such as lactose, which may bepresent in a smaller, equal, or greater amount than the activeingredients, for example in from 50 to 150 percent by weight of thecompound of formula I and such other active ingredients as may bepresent.

Whilst the inhalation of medicament has been described above withparticular reference to oral administration, it will be appreciated thatit may be desirable to administer the medicament nasally. The terminhalation is therefore used herein to denote, where the contextpermits, both oral and nasal administration.

The composition of the invention may also be administered as tablets,syrups and the like or by intradermal or intravenous injection in theconventional manner.

The compounds of formula I may also find use in the treatment of eyeconditions, for example that associated with hayfever. Eor such use thecompound of formula I may be used in the form of an eye drop as anaqueous solution containing about 2 percent of the compound and apreservative.

In addition to the internal administration, the compounds of formula Ifind use in compositions for topical application, e.g. as creams,lotions or pastes for use in dermatological treatments.

In addition to the compound of formula I and the ingredients required topresent the compound in a form suitable for the selected mode ofadministration, other active ingredients may be present in thecomposition of the invention. Thus, in compositions for administrationby inhalation, it may be beneficial to include a brochodilator. Anybronchodilator may, within reason, be used. Suitable bronchodilatorsinclude isoprenaline, adrenaline, orciprenaline, isoetharine andderivatives thereof, particularly the salts thereof. The use ofisoprenaline sulphate is preferred. The amount of bronchodilator usedwill vary over a broad range, depending, inter alia, upon the nature andactivity of the bronchodilator and the compound of formula I used.However, the use of a minor proportion (ie less than 50 percent byweight) of the bronchodilator is preferred. The use of from 0.1 topercent by weight of the bronchodilator based on the weight of thecompound of formula I is particularly preferred.

From a further aspect, the invention therefore provides a compositionwhich comprises a compound of formula I or a derivative thereof inadmixture with a bronchodilator, which latter is preferably present inless than 50 percent, especially 0.1 to 10 percent by weight of theformer.

As indicated above, the compounds of formula I are indicated for use ininhibiting the effects of antibody-antigen reactions. In such treatment,the compound or composition of the invention is administered by thechosen method to the site of the antibody-antigen reaction in thetherapeutically effective amount. The treatment may be one whichrequires repeated dosages of the medicament at regular intervals. Theamount and frequency of medicament administered will depend upon manyfactors and no concise dosage rate or regimen can be generally stated.However, as a general guide, where the compounds are administered byinhalation to a patent suffering from acute allergic asthma,therapeutically useful results may be achieved when the compounds areadministered at a dosage of 0.1 to 50 mgs. Where the compounds areadministered by the oral route, larger dosages may be given.

The invention thus also provides a method for inhibiting the effects ofan antibody-antigen reaction which comprises the prior or subsequentapplication to the known or expected area of the antibody-antigenreaction mechanism of a therapeuti cally effective amount of a compoundof formula I or a derivative thereof.

The compounds of formula I may be prepared by a variety of methods.These will usually involve the steps of introducing the substituents P,Q, T, P Q, and T the formation of the pyrone rings on each half of themolecule and the linkage of the two halves of the molecule. These stepsmay take place in any order where the nature of the reaction conditionsand reactants permits. Thus, some but not all of the substituents may beintroduced into each of the benzene rings; these benzene rings may thenbe converted to chromone nuclei; these chromone nuclei then linked; andfinally the last of the substituents introduced.

It will be appreciated that the compounds of formula I possess twopyrone rings and that these may be the same or different. Each of theserings may be introduced in separate stages by different or similarmethods or may be introduced together in a single reaction stage. It isalso possible to introduce in separate stages a precursor of one of thedesired rings, for example a chain CO-CH --CH(COOH)O,

by one method, to introduce the same or another precursor for the otherring, e.g. a chain COCH(CI-I CH(COOI-I)-.O,

by a different method; and then to convert the two precursors into thedesired rings in a final common reaction stage, e.g. dehydrogenation.For convenience the preparation of the compounds of formula I will bedescribed in terms of the formation of only one of the two desiredpyrone rings. The other ring may be present initially, be formed duringthe formation of the first ring, or be introduced later by the same or adifferent process. Where both rings are to be introduced one afteranother it may be necessary to shield or block the sites at which thesecond ring is to be introduced. Such shielding or blocking may beachieved by conventional methods.

Furthermore the two chromone moieties which are linked via the X linkagemay each be formed before or after the linkage of the two benzene ringshasv been effected. Thus, one chromone nucleus may be formed, this thenlinked to an appropriately substituted benzene ring which is thereafterconverted into the second chromone nucleus.

The starting materials from which the compounds of formula I may beprepared may be defined as being those of the general formula whereinthe pair of groups A and A either together form the chain COCR C(COOH)-Oor a derivative thereof or form the pair of groups A and A whichrepresents a chain or a pair of groups (one of which may be hydrogen)convertible either directly or via another chain or pair of groups to aCOCR C(COOI-I)O chain or derivative thereof; one of B, B B or Brepresents a group L and the others are each selected from hydrogen orsubstituents other than hydrogen (i.e. the desired P-T groups,precursors therefor or derivatives thereof); and L is either a group toform the desired X- linkage or a precursor therefor.

The methods for preparing the compounds of formula I may be generallydefined as comprising conversion of such groups A and A and L as may bepresent in a starting material of formula ll into the desired COCRC(COOH)O chain or derivative thereof and the desired I group orderivative thereof respectively. Where the compound I] is not a linkedcompound, the process for preparing the compounds of formula I willinvolve at some stage the reaction of a compound of formula withconversion of either or both pairs of groups A and A (if these are thepairs of groups A and A") to the desired --CO CR C(COOH)-O- chain or aderivative thereof.

For convenience, the linkage and pyrone ring formation will be describedherein as separate processes, although it will be understood that thisseparation is arbitrary and that it is possible to carry out part of theformation of either or both pyrone rings then to effect linkage andthereafter to complete ring formation.

It will be appreciated that precursors of the above compounds, that iscompounds which react under the conditions of the reaction as the abovecompounds, may be used. Thus, for example an acetoxy derivative of aphenollic hydroxy group in a compound may be used in place of the freehydroxy group. It is to be understood that in the following process forpreparing the compounds of formula I active precursors may also be usedwhere appropriate.

The conversion of a pair of groups A and A in a starting material offormula II may be achieved in a number of ways. Thus, the desired pyronering may be formed by cyclizing compounds of the general formulas:

B COCHRICOCOIU B5 OM COOMI B1 1 (EOOMI B4 and VII II m (mum on (M B9 OM[wherein R is an OM, group or a group convertible thereto, M is hydrogenor an alkali-metal cation and M is an M group or an alkyl group], withoxidation or dehydrogenation of the product if required. The desiredpyrone ring may also be formed by modification of an alreadyformedchromone or chromanone compound (i.e. compounds of formula II wherein Aand A together form the chain -COCR C(D)O or COCHR-CH(D)-O, wherein D isa COOM group or a group D which is convertible to a COOH group orderivative thereof) for example by oxidation of substituents in the2-position of the ring or by dehydrogenation.

The compounds of formula V may be readily cyclized, for

example by heating directly or in a solvent such as ethanol,

glycerol or dioxan. Cyclization may be carried out under neutralconditions or in the presence of an organic base such as pyridine.However, it is preferred to carry out cyclization in the presence of acyclization agent and also desirably in an organic solvent medium, suchas ethanol. Ideally the acid cyclization agent is an acid such as apolyphosphoric acid, sulphuric acid, hydrochloric acid, acetic acid,toluene psulphonic acid or mixtures thereof. Water may be present in thecyclization reaction mixture, as when concentrated aqueous acid is usedas the cyclization agent. When a compound of formula V is used wherein Mis an alkyl group, simultaneous cyclization and dealkylation may beachieved by the use of hydriodic or hydrobromic acid as the cyclizationcatalyst.

Cyclization may be carried out at from ambient temperature to about100C, for example by heating the reaction mixture on a steam bath and,where the nature of the reaction medium permits it, under reflux.

As indicated earlier, the group R in the compound of formula V is an OHgroup, or a group which is convertible to an OH group. Such conversionmay have already occurred in the cyclization of the compound or may havetaken place prior to cyclization. However, where this is not the case,such conversion may be readily achieved using conventional methods.

Alternatively, the R group may be converted into a more desirablederivative, for example an alkoxy group, and such further conversion isalso within the scope of this invention.

The compounds of formula V may themselves be prepared by a number ofmethods. For example, a compound of the formula:

VIII

C O CHiR (wherein R has the values given above and M is hydrogen, analkali-metal cation or an alkyl group, such as a lower alkyl group, e.g.a methyl, ethyl, propyl or pentyl group), may be condensed with acompound of the formula R CZ-CZR wherein R and R may be the same ordifierent, one being a group reactive with an hydrogen in the 'CO-CI-I Rgroup of the compound VIII, the other being an R group, and each Z is acarbonyl oxygen or one may represent two halogen atoms and the other isa carbonyl oxygen. Suitable groups which react with a -COCI-I R groupinclude alkoxy], amino, alkylamino, substituted amino or substitutedalkylamino groups. It will be appreciated that these groups in cludegroups which are also convertible to OH groups. Where R and/or R isasubstituted amino group, the nitrogen atom may carry one or two groupsE, wherein E is a lower alkyl, a substituted or unsubstituted aryl,alkaryl or haloaryl group. In the case where the nitrogen carries onlyone group E the substituent may be linked to the nitrogen through an SOgroup. Examples of suitable compounds for present use include those ofthe general formulas R"OOCCOOR (wherein each R is an alkyl group, suchas methyl, ethyl, propyl, butyl, pentyl group; an aralkyl group such asa benzyl group; or an alkenyl group such as an ally] group); and R OC(I*lal) -COOR (wherein Hal is halogen, preferably chlorine or bromine).Preferred compounds of formula R"CZCZR for present use include diethyloxalate, ethyl ethoxydichloroacetate, ethyl oxamate, ethyl oxalylanilideand ethyl oxalyl-toluene -psulphonamide.

The condensation of the compound VIII with the compound of formula RCZ-CZR may be carried out merely by mixing the reactants together andheating, if desired, to a temperature of from 25 to 150 C, preferablyabout 70 to 80 C. In the case of the oxalate esters, the reaction isdesirably carried out in the presence of a condensation agent. Suitableagents include, for example, metal alkoxides, such as sodium ethoxide,sodium hydride, sodamide or metallic sodium. The condensation agent maybe formed in situ, for example by the use of ethanol as the reactionmedium and the addition of metallic sodium. In some cases thealkali-metal salt of the compound of formula VIII (that is when M isalkali-metal) may act as part of the condensation agent required. Wherea substituted dihaloacetate is used, it may be preferred to carry outthe reaction in the presence of a finely divided metal catalyst, such asa finely divided platinum group metal.

If desired, the reaction may be carried out in an inert solvent ordiluent medium, such as diethyl ether, dioxane, ethanol, benzene,toluene, tetrahydrofuran, or mixtures thereof.

Whilst the reactants may be employed in substantially stoichiometricproportions, it will usually be preferred to use a substantial excess ofthe compound RCZCZR. When used, the condensation agent is desirably usedin from 200 to 750 molar percent based on the amount. of the compound offormula VIII used, preferably from 200 to 500 molar percent.

It will be appreciated that the condensation reaction is desirablycarried out under substantially anhydrous conditions.

The reaction mixture of the above reaction will usually contain thecompound of formula V, or a precursor thereof, though in some casescyclization of the product to the chromone-2 carboxylic acid, or a saltor derivative thereof, may take place spontaneously. Cyclization of thecompound of formula V may also be achieved in situ by acidifying thereaction mixture. It is usually preferred to recover the compound offormula V from the reaction mixture and to cyclize it in the presence ofa cyclization agent, optionally in the presence of a small amount ofwater, as described above. The compound may be recovered from the crudereaction mixture wherein it was prepared by conventional techniques. t

The compound of formula V may also be prepared by the reaction of acompound of formula VIII wherein M is hydrogen or an alkali-metal cationwith a dicarbonyl compound of formula RCOCOR wherein R and R have thevalues given above, except that one or both of R" and R are halogen.Suitable dicarbonyl compounds for use in this case include oxalylchloride and compounds wherein R is chlorine or bromine and R is anOI-I, alkoxy (e.g. methoxy or ethoxy), NHg, phenylarnino or toluene-psulphonyl-amino group. The reaction using these halo compounds may becarried out in a manner similar to that described in relation to the useof the other compounds R" CZCZR except that an acid-binding agent isused in place of the condensation agent and that the use of an anhydrousorganic solvent is desirable. Suitable dicarbonyl compounds for use inthis case include oxalyl chloride and compounds wherein R is chlorine orbromine and R is an OH, alkoxy (e.g. methoxy or ethoxy), NH,,phenylamino or toluene -psulphonyl-amino group. The reaction using thesehalo compounds may be carried out in a manner similar to that describedin relation to the use of the other compounds RCZCZR", except that anacid-binding agent is used in place of the condensation agent and thatthe use of an anhydrous organic solvent is desirable.

Suitable acid-binding agents include alkalis, such as sodium orpotassium carbonate; alkali-metal alkoxides, e.g. sodium alkoxide; andorganic amines such as pyridine or triethylamine. The acid-binding agentis present in at least the theoretically stoichiometric amount to bindall the halogen in the dicarbonyl compound. It may be desired to use anexcess of acid-binding agent, and if desired, the acid-binding agent maybe added to the reaction mixture in a series of additions over a periodof time. In some cases the acid-binding agent may be used as thereaction medium. The reaction mixture from this process will usuallycontain the intermediate product of the formula or a precursor orderivative thereof, though in some cases rearrangement of thisintermediate to yield the compound of formulaV may have occurredspontaneously. Furthermore,

where an acid chloride such as oxalyl chloride is reacted with directly.Rearrangement of the intermediate may also be achieved in situ byheating in a medium such as glycerol, optionally in the presence of analkali. However, it is usually preferred to recover the intermediateproduct from the reaction mixture and rearrange it, after anypurification that may be desired, in a separate reaction step. Therecovery and purification of the intermediate product may be achieved byconventional methods.

Rearrangement of the intermediate product may be achieved by heating thecrude, or purified, recovered material under non-acidic conditions andpreferably in an inert solvent or diluent medium such as benzene,dioxan, anisole or the like. The non-acidic conditions may be achievedby the presence of a base, such as pyridine, or of a mineral alkali suchas potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydride, sodium alkoxides, e.g. sodium methoxide, or metallic sodium. Ifdesired, the rearrangement may be carried out under the influence ofheat, for example at from ambient temperature to C, (e.g. by heating ona steam bath and, where the reaction mixture permits it, under reflux.Preferably the re-arrangement is carried out under substantiallyanhydrous conditions, i.e. in the absence of significant amounts ofinitial or added water. The amount of alkali present may be from 100 to1000 molar percent, based on the amount of the intermediate productbeing rearranged and may, if desired, be added in a single addition orin a series of additions over a period of time.

The compound of formula V or a derivative or precursor thereof, may berecovered from the reaction mixture in which vll it was formed byconventional methods with, if necessary, conversion of the R group intoa more desired substituent as outlined above.

In a further process for preparing the compounds of formula V, anappropriately substituted salicylic acid or ester thereof is reactedwith a compound of the formula CH CO COOR", wherein R has the valuesgiven above. The reaction is desirably carried out in an inert mediumsuch as ethanol, anisole, benzene or dioxan and it is preferred toemploy a condensation agent such as an alkali-metal alkoxide (e.g.sodium ethoxide), sodamide, sodium hydride or metallic sodium.

The compounds of formula VI may be cyclized by treating the compoundwith a cyclization agent at ambient temperature or above. Suitablecyclizing agents include dehydrating agents concentrated acids such aspolyphosphoric acid, sulphuric acid, chlorsulphonic acid and other Lewisacids. It will be appreciated that, since cyclization is achieved inthese cases by the use of dehydration agents, the presence of added orinitial water in the reaction mixture is undesirable. It is usuallypreferred to subject the compounds of formula VI.to an initial dryingstep and to carryout the cyclization reaction under substantiallyanhydrous conditions.

Alternatively, cyclization may be achieved by converting the freecarboxyl groups of the compound of formula VI into acyl chloride groups,for example by treatment with PCl PCl, or SOCI and subjecting theresultant acyl chloride to an internal Friedel Crafts reaction.

The compounds of formula VI when R is hydrogen may be obtained by thereaction of a compound of formula:

OMI

(wherein M is hydrogen or an alkali-metal cation) with an acetylenedicarboxylic acid or ester thereof under alkaline conditions to producea product which, upon hydrolysis, yields the compound of formula VI. Theacetylene dicarboxylate esters may be derived from alcohols having fromone to ten carbon atoms. However, since the ester moiety is to beeliminated, it is preferred to use simple esters derived, for example,from methyl, ethyl, propyl, or butyl alcohols. It is preferred that bothcarboxylic acid groups on the acetylene dicarboxylic acid be esterified.In this process the ester and compound IX are reacted, preferably inapproximately stoichiometric amounts, under alkaline conditions. Thesemay be achieved by the presence of an organic base such as benzyltrimethyl ammonium hydroxide, or of an alkali-metal hydroxide. However,it is convenient to have the alkali present in the form of analkali-metal salt, especially the sodium salt, of the compound IX, sucha salt being considered as free compound when assessing the amount ofcompound IX present in the reaction mixture. Where this is done, thealkali-metal salt of compound IX may conveniently be made in situ in thereaction mixture by the addition of metallic sodium. The alkali isbelieved to act catalytically and it is possible to use less than 100molar percent thereof based on the amount of compound IX present. Weprefer to use from 5 to 20, preferably about 10, molar percent. It willbe appreciated that the reaction, especially where the alkali-metal saltis formed in situ, is desirably carried 'out under substantiallyanhydrous conditions. It is also preferred to carry out the reaction ina solvent or diluent medium. Suitable media include, for example, anexcess of compound IX, diphenyl ether, dioxan and anisole. These mediahave the advantage that the reaction may be carried out at elevatedtemperatures at atmospheric pressure. It is generally preferred to carryout the reaction at temperatures offrom 50 C to 150 C.

In place of the acetylene dicarboxylate ester used in the above processfor the preparation of the compound of formula VI, an ester of amono-halofumaric acid, or a precursor thereof may be used, i.e. ester ofacids of the general formula:

wherein R is halogen and R is an R group when R and R together form acarbon to carbon bond; or R is halogen and R is an R gr I- P, nd one ofthe other two is hydrogen and the second is halogen. In this casethereaction is not an addition reaction but a condensation reaction whichinvolves at some stage the elimination of the elements of a halogen acidfrom between the compound IX and the halofumarate ester. This halogenacid must be eliminated from the system and the reaction is thereforecarried out in the presence of at least sufficient of an acid-bindingagent to eliminate the elements of the halogen acid which will be formedduring the overall process. The elements of the halogen acid are notnecessarily eliminated in one step, but may be eliminated firstly as aproton and then as an halogen anion. The term acid-binding agent istherefore used in this context to denote both conventional acid-bindingagents, such as pyridine and triethylamine, and materials whicheliminate for example, first the hydrogen from the compound IX (to forma saltthereof) and then are displaced from the organic salt to form aninorganic salt with the halogen of the halofumarate ester. Apart fromthe use of a different acid ester reactant and the presence of theacid-binding agent, the process may be carried out in similar manner tothat when an acetylene dicarboxylate ester is used. Since theacid-binding agent is usually also a strong alkali, there is generallyno need to provide a separate strong alkali in the reaction mixture. Aswill be appreciated from the general for,- mula for the acids which maybe used to react with the compound IX, the use of the monohalofumarateester or precursors thereof permits the introduction of an R group intothe molecule.

As indicated above, it is also possible to use compounds which yield thedesired halofumarate esters under the conditions of the reaction withthe compound IX. Such other compounds or precursors, include halomaleateesters and dihalosuccinate esters. When precursors are used, it may benecessary to provide extra alkali to ensure conversion of the precursorto the desired halofumarate ester. Such alkali may be merely an excessof the acid-binding agent.

The products obtained from the reactions outlined immediately aboveusually contain the compounds of formula VI in the form of their esters.The compounds of'formula VI may be recovered from these products byacidification of the reaction mixture, hydrolysis of the esters byboiling with alkali and acidification to liberate the free acid andextraction of the equeous solution with, for example, ether which maythereafter be evaporated. The product may, if necessary, be subjected tofurther purification, for example, by extracting the ethereal solutionwith sodium bicarbonate and then precipitating the acid of formula VI byaddition of dilute sulphuric acid.

The compounds of formula VII may be cyclized by treatment with an alkalior organic base in a suitable inert solvent to give a2-carboxychromanone compound. This may subsequently be converted intothe 2-carboxychromone compound by oxidation or dehydrogenation or byhalogenation followed by dehydrohalogenation as described below.Simultaneous oxidation and cyclization to the desired 2-carboxychromonecompound may be brought about by the introduction of a suitable oxidantinto the cylization stage (e.g. selenium dioxide in an inert solvent).

The compounds of formula VII may be prepared by reacting a compound offormula VIII wherein M is hydrogen or an alkali-metal cation withglyoxalic acid or an ester thereof in the presence of a base (e.g.aqueous sodium hydroxide) or a mineral acid. A water miscible solvent,e.g. alcohol, may be added to facilitate the reaction.

Alternatively, a compound of formula IX wherein M is hydrogen is heatedat a temperature of, for example, 25 to 150 C with maleic anhydride in asolvent or diluent medium, such as nitrobenzene or carbon disulphide, inthe presence of a Lewis acid, such as an excess of aluminum chloride.The complex which is produced by this process may then be decomposedwith a dilute mineral acid, such as hydrochloric acid, and the solventremoved, for example by distillation or steam distillation. The residue,which contains the compound of formula VII wherein M is H, may berecovered using conventional techniques and then purified by, forexample, recrystallation. However, the reaction may proceed to give a2-carboxychromanone directly without isolation of an intermediate.

In the processes outlined above, we believe that the compounds V to VIIare all necessary intermediates in the conversion of the variousstarting materials to chromone-Z-carboxylic acids or derivativesthereof. However, in many cases the intermediates are formed under thoseconditions required to achieve cyclization and therefore exist onlytransitorily. Whilst, for clarity, these processes have been describedas if the compounds V to VII were necessarily isolated prior tocyclization the invention embraces those processes wherein theintermediate undergoes cyclization without separation or isolation fromthe reaction mixture in which it has been prepared.

As indicated above, the desired compound of formula I may also be formedfrom a compound already containing a nucleus, i.e. from a compound offormula B l l wherein D is a group which is convertible to a COOH groupor a derivative thereof. Examples of suitable D groups include nitrile,amide and ester groups which may be hydrolyzed to a carboxylic acidgroup; alkyl or substituted alkyl groups such as methyl, hydroxymethyl,halomethyl e.g. chloromethyl, bromomethyl, dichloromethyl,trichloromethyl), acyl groups such as formyl or acetyl groups, andalkenyl and aralkenyl groups such as vinyl, w-trichloromethylvinyl andstyryl groups, all of which are groups oxidizable or hydrolyzable to acarboxylic acid group. The conversion of the D group to a COOH group orderivative thereof may be achieved using any of the known methods.

The compounds of formula X may be prepared by a variety of methods, manyof which are closely analogous to the processes described above for thepreparation and cyclization of the compounds of formulas V to VII exceptthat in place of the starting materials V, VI and VII compounds of theformu- 6O and XIII

are used and that the final product requires conversion of the D groupto the COOH group or derivative thereof. Such analogous processes maytogether be broadly described as a process for preparing a compound offormula I by conversion of a compound of the formula [wherein A and Aare the pairs of groups COCHR COD and OM; H and --OC(D) CRCOOM; or CO-CR CHD and OM respectively and D, M, M, R, B, B B and B have the valuesgiven above] during which cyclization of the groups A and A takes place.

Thus, the compounds of formula X may be prepared by cyclizing a compoundof formula XI under the conditions described above for the cyclizationof the compound of formula V. In some instances cyclization may occurspontaneously.

The compounds of formula XI may themselves be prepared by condensing acompound of formula VIII with a compound of formula D'COR, wherein D hasthe values given above and R is a group reactive with a hydrogen in theCOCH R group of the compound VIII. Suitable compounds DCOR includeesters and amides or substituted amides of substituted or unsubstitutedacetic and cinnamic acids and the like, e.g. a compound of the formula(MO) CHCOOM such as ethyl 4O diethoxyacetate. The condensation may beachieved by the methods outlined earlier for the production of thecompounds of formula V from the compound VIII and the compounds RCZ--CZR.

The compounds XI may also be prepared from the compound VIII and thecompounds DCOR wherein R is halogen via, if necessary, the rearrangementof-a compound of the formula:

B 00 CD using conditions similar to those set out above for thepreparation of the compounds of formula V by the analogous route.

Particular examples of the preparation of compounds XI include thepreparation of those compounds wherein D is a methyl group by reactionof an alkyl acetate, i.e. the compounds DCOR wherein D is a methyl groupand R is an alkoxy group, with a compound VIII under the condensationconditions outlined above for the preparation of the compounds V.

The styryl compound of formula XI, that is where D is may be preparedfrom the compound VIII by reaction with sodium cinnamate and cinnamicanhydride using a Kostanecki Robinson synthesis, or by reaction with acinnamoyl halide, e.g. cinnamoyl chloride, in the presence of anacid-binding agent to yield the cinnamate ester of the compound VIII,followed by rearrangement with a base, e.g. potassium carbonate, in thepresence of an inert solvent such as toluene or benzene, to give thecompound XI of the formula:

wherein Ar denotes a benzene ring.

From these examples of the preparation of the compounds of formula XI itwill be appreciated that certain of the processes for preparing thecompounds of fonnulas V and XI may together be broadly described asprocesses wherein a compound of formula VIII is reacted with a compound.

wherein R is a group reactive with an hydrogen in the COCI-I R group ofthe compound VIII, each Z is a carbonyl oxygen or one may be two halogenatoms when the other is a carbonyl oxygen, n is I or 2 and when n is I,W is a D group i.e. a COOM group or a group D convertible to a COOI-Igroup or a derivative thereof, and when n is 2, W is sn R group, i.e. anOI-lgroup or a group convertible thereto.

The compounds of formula XII may be prepared by the reaction of acompound of formula IX with a substituted acetylene monocarboxylic acid,or ester thereof in a manner similar to that used to prepare thecompounds of formula VI above. The acetylene monocarboxylic acids, oresters thereof, for present use have the general formula D'C E C-COOMwherein D and M have the values given above. It is preferred that M be alower alkyl group, such as a methyl or ethyl group. It is also possibleto use precursors of acetylene monocarboxylic acids or esters, forexample the mono-halo-ethylenic and dihaIo-ethane analogues thereof.

The compounds of formula XII may be cyclized in a manner similar to thatemployed with the compounds of'formula VI. As with the compounds offormula V and XI, the preparation of the compounds of formula VI and XIImay together be broadly described as a process wherein a compound offormula IX is reacted with a compound of the formula R'*, R", R, R' andD have the values given above and also the further value that when R andR together form a carbon to carbon bond, R and R may also form a carbonto carbon bond.

The compounds of formula XIII may also be prepared and cyclized in amanner similar to that used to prepare and cyclize the compounds offormula VII. Thus, a compound of formula VIII may be reacted with analdehyde of the formula OHCD, for example cinnamaldehyde, undersubstantially the same conditions as are used to prepare the compoundsof formula VII from glyoxalic acid. However, it may be preferred toemploy compounds of formula VIII wherein M is an alkyl group and todealkylate the reaction product to obtain the compound offormula XIII. 7

As with the other intermediate compounds, certain routes for thepreparation of the compounds of formula VII and XIII may together bebroadly described as comprising the reaction of a compound of formulaVIII with a compound of the formula OHCD wherein D has the values givenabove.

In addition to the direct conversion of a compound of formula X into thedesired compound of formula I, the D group in compounds of formula X maybe converted in known manner from one form of substituent into anothermore preferred substituent, D which is then converted to the desiredCOOI-l group or derivative thereof.

' stituent Thus, the compound of formula X wherein D is a methyl groupalso serves as an intermediate in the preparation of a member of otheroxidizable derivatives. For example, the methyl group may be convertedinto an halo-methyl group, e.g. by reaction with hydrogen chloride andmanganese dioxide in boiling acetic acid to produce the chloromethylgroup; or by reaction with bromine in acetic acid to yield a bromomethylgroup. The halomethyl group may be oxidized to a carboxylic acid groupusing, for example, chromium trioxide as oxidizing agent in the presenceof acetic acid.

The methyl group may also be reacted with p-nitrosodimethylaniline andthe reaction product hydrolyzed with dilute mineral acid to give a Cl-IOgroup which may oxidized to a carboxylic acid group using, for example,chromium trioxide as reagent. Condensation of a methyl group with abenzaldehyde in the presence of a condensation catalyst gives a styrylgroup which may be oxidized to a carboxylic acid group using, forexample, potassium permanganate.

The CI-IO group may serve as a starting point for the preparation of aCN group, e.g. by reaction with hydroxylamine to yield an oxime whichmay be dehydrated to give the CN group. This may then be hydrolyzed to acarboxylic acid group or amide thereof, under acid conditions.

As stated earlier, the chromone-Z-carboxylic acids may be prepared byconversion of a chain CO-CHRCI-I(D) O to the desired COCR C(COOI-I)O-chain. This conversion may go via a compound of formula X when the groupD is a group D', or may proceed directly to the chromone-2-carboxylicacid or a derivative thereof. Thus, the chromone-Z-carboxylic acids mayalso be prepared from corresponding chromanone compounds bydehydrogenation followed, or preceded, by oxidation or hydrolysis of anysubin the 2-position, if this is necessary. The dehydrogenation may beeffected by, for example, the use of selenium dioxide, palladium blackorchloranil. Alternatively, dehydrogenation may be carried outindirectly by halogenation followed by dehydrohalogenation. Thus, thechromanone may be brominated using N-bromosuccinimide in an inertsolvent or by treatment with pyridinium perbromide in an inert solventsuch as chloroform in the presence of a free radical catalyst such asbenzoyl peroxide, to yield the 3-br0mo derivative which may subsequentlybe dehydrobrominated. The chromanones themselves may be obtained by theaction of a 'y-substituted 'y-chloropropionic acid or derivative thereofon a compound of formula IX in the presence of a basic reagent, followedby conversion of the acid function to the acid I chloride and treatmentwith .aluminum chloride in the presence of a suitable solvent (e.g.nitrobenzene); or by the action of a compound of formula IX on aB-substituted acrylonitrile, with subsequent hydrolysis and cyclizationof the product. As indicated above, cyclization of the intermediates VIIand XIII may lead to the production of a corresponding chromanonecompound, which may then be converted-as outlined above to the desiredchromone compound.

In addition to the above outlined methods for preparing thechromone-2-carboxylic acids via the intermediates V to VII and X toXIII, other methods may be devised which do not necessarily produce anyof these intermediates. Thus, an acetyl halide, acetic anhydride oracetic acid may be condensed with an oxalate ester of the type ROOCCOORwherein R is an aryl group and R is an alkyl or an aryl group, thecondensation being carried out in the presence of a Lewis acid. Theoxalate ester may itself be obtained by the esterification of a compoundof formula IX with the appropriate oxalyl halide. A further processwhereby the chromone-2-carboxylic acids may be obtained is one wherein acompound of formula IX is heated with an alkyl alkoxalylacetate, such asethyl ethoxalylacetate, optionally in the presence of a dehydratingagent such as phosphorus pentoxide.

The pairs of groups A and A may also form a chain which may be convertedinto a pair of groups from which the desired COCR C(COOI-I)O chain maybe derived. Thus A and A may form a chain O-COCH CT'- (where "I is analkyl, e. g. methyl, or aryl group) which may be cleaved by treatmentwith an alkali or hydrazine to yield a compound wherein A is OH or aderivative thereof and A is hydrogen.

From the above example of the conversion of the groups A and A into thedesired CO-CR C(COOH)O chain or a derivative thereof, it will be seenthat many of these routes may be together broadly described as theconversion of compounds wherein A and A form the pairs of groups OM andH or COJ; H and OCD CRCOOM; OCOCOR" and H or COCH R respectively[wherein J is a group cH R, OM, -CHRCOD or CR CHD, and R, R, D and Mhave the values given above] or wherein A and A together form a chainCO-CR C(D) O, COCHRCH(D)O or OCOCH C'l' (T being an alkyl or arylgroup).

The processes outlined above may produce the free acids of formula I ormay yield derivatives thereof. It is also within the scope of thepresent invention to treat the product of any of the above processes,after any isolation and purification steps that may be desired, in orderto liberate the free acid therefrom or to convert one, form ofderivative into another. The methods used to isolate and purify anyproduct may be those conventionally used, Thus, salts may be prepared bythe use of alkaline conditions during the recovery and purification ofthe compound. Alternatively, the free acid may be obtained andsubsequently converted to a desired salt by neutralization with anappropriate base, e.g. an organic amine, or an alkali such as analkali-metal or alkaline-earth metal hydroxide, carbonate orbicarbonate, preferably a mild base or alkali such as sodium carbonateor bicarbonate. Where the compound is recovered in the form of a salt,this salt may be converted to a more desirable salt, for example by ametathetical process. The esters may be obtained as a result of havingused appropriate starting materials, for example by the reaction of adialkyl oxalate with a compound of formula Vlll as hereinbeforedescribed; may be formed by the reaction of an appropriate alcohol,alkyl sulphate or halocompound with free carboxyl groups in the compoundI; or may be formed by the reaction of an appropriate alcohol with anacyl halide of the compound of formula I. Alternatively,transesterification techniques may be used to exchange one ester groupfor another. The amides may be readily obtained, for example, bydehydration of the ammonium salt or by reaction of an ester or acylhalide with an appropriate amino compound such as ammonium hydroxide ora primary or secondary amine or an amino acid. Alternatively, the freeacid of formula I may be condensed with an alkyl haloformate-(eg.chloroformate) in the presence of an organic base such astriethylamine', to yield a mixed anhydride which is then treated with anamino-acid or ester thereof in the presence of a suitable solvent togive an N- carboxyalkyl substituted amide. The mixed anhydride need notbe isolated from the reaction mixture in which it was prepared, but maybe treated in situ.

As indicated above, the general formula II for the starting material isintended to relate not only to compounds containing only one benzenering but also to compounds which already possess the two rings linked byan X linkage. Where the starting material is not already linked, suchlinkage may be achieved by a variety of methods depending upon thenature of the X linkage, and at any suitable point during the productionof the compounds of the invention. Moreover, the linkage group or atom Xmay be introduced into one molecule of the starting material which isthen treated to convert the A and A groups partially or wholly to thedesired CO-CR C(COOH)-O- chain and a further molecule of startingmaterial or a chromone nucleus then attached to the free end of thelinkage atom or group X. For convenience, the methods of forming the Xlinkage will be described in terms of linking two molecules of the samestarting materials ll through the B positions in a single process, i.e.by reacting the compounds III and W referred to earlier. It will beunderstood that in many cases the initial linkage produced may be aprecursor of the desired linkage, as when substituents are to be presentupon the desired final linkage. The intermediate linkage may beconverted to the desired form using the appropriate conventionaltechniques. For example, the hydroxy group of an hydroxy methylenelinkage may be converted to an alkoxy group, a halogen group, an estergroup or an hydroxyalkoxy group by reaction with an alkyl halide, PCl orPCl an acid halide or an alkylene oxide respectively.

Where the X- linkage is to be a carbon to carbon bond, such a linkagemay be achieved by an Ullmann reaction in which two molecules of thestarting material of formula II where B is halogen, notably iodine, areheated with copper. Where the linking group is to be an O- group, such alinkage may be formed by reacting a starting material wherein the Bsubstituent is halogen (i.e. a compound of formula Ill where L ishalogen) with a molecule 'of a second starting material wherein the Bsubstituent is an OH group (i.e. a compound of formula IV wherein L isOH), or an alkali metal salt thereof. Alternatively, other pairs ofstarting materials may be used where the B substituents are such thatthey yield an ether linkage upon reaction with one another, for examplewhere one B substituent is an anion-forming group such as a tosylate ormethyl sulphonate group and the other is an OH group, a salt thereof oran active precursor thereof such as an acetoxy group. Where the linkinggroup is a sulphur atom this may be formed by reacting a startingmaterial wherein the B substituents are hydrogen with thionyl chloridein the presence of a metal, such as copper bronze, or with sulphurdichloride. The compounds containing an -S linkage may be oxidized toyield compounds having --SO and SO,, linkages. The sulphone linkage mayalso be formed by reacting sulphonyl chloride or chlorosulphonic acidwith the appropriate starting material. Alternatively, chlorosulphonicacid may be reacted with an appropriate starting material to yield anaryl sulphonyl chloride which may then be reacted with another moleculeof the starting material to yield the desired linked compound.

The methylene linkage may be formed by the condensation of, say,resacetophenone with di-iodomethane under alkaline conditions in thepresence of an inert solvent or diluent. Alternatively, an appropriatephenol may be condensed with formaldehyde. The substituted methylenelinkages may be readily obtained, for example, via the haloorhydroxymethylene linkages as outlined above or by the condensation of analdehyde with two molecules of the same or different phenols. Thecarbonyl linkage may be obtained by a Friedel Crafts reaction using anappropriately substituted benzoyl chloride and an appropriatelysubstituted benzene. Alternatively, the carbonyl linkage may be formedby reacting an appropriately substituted phenol having the position parato the hydroxy group free with an appropriately substituted benzoic acidin the presence of at least 10 mols of anhydrous liquid hydrogenfluoride per mol of phenol, the reaction being carried out at from 20 toC.

The NH linkage may be achieved by the elimination of the elements ofammonia between two molecules of an aminosubstituted starting material.

The substituted nitrogen linkages may readily be prepared from the NHlinkages using conventional techniques.

In the above examples of methods by which the -X linkage may beachieved, it has been assumed that the linkage process will not affectany groups already present and that the introduction of other groupsinto the linked product (such as either or both of the pyrone rings orother substituents on the benzene rings) will not detrimentally affectthe linkage X. However, where this is not the case, it may be necessaryto shield or block susceptible groups, for example by alkylation,acetylation or benzylation, or to block the intended site of such agroup with a cyano or nitro group which will remain unaffected duringthe reaction process and may thereafter be removed to leave a freeposition into which a substituent may, if desired, be introduced. Theconcept of blocking or shielding susceptible sites or groups is ofespecial relevance in those cases where, for example, linkage orcyclization could occur in two forms, giving rise to by-products. Theshielding or blocking may be achieved by any of the conventional methodsand the desirability of carrying out such shielding or blocking will bereadily apparent. Reference to particular instances of blocking orshielding of groups has not therefore been made in the presentspecification, it being understood that such steps will be applied wheredesirable and that the processes of the invention will, whereappropriate, include such steps and the steps necessary to free theshielded site or group. It is also within the scope of this invention,therefore, to introduce one or more of the substituents P, Q, T, P,, Qor T at a stage intermediate to or subsequent to introduction of the X-linkage or either or both of the pyrone rings.

The formation of the X linkage by reaction of the compounds III and IVmay take place in more than one stage, notably where the units to belinked are different or where the linkage is to carry substituents asindicated above. It may therefore be desirable to block or shieldreactive groups other than that upon which reaction is required whenintroducing the group L in to a compound of formula III.

In addition to providing the novel compounds of formula I,

the invention also provides as novel compounds the inter-- mediate ofthe formula wherein B and B are the groups P-T and Ifl-T or are blockedor shielded sites therefor or precursors or derivatives of the desiredP-T and P -T groups; P, Q, T, P,, Q and T have the values given above; Xis an X group or a precursor or derivative of the desired group; thepair of groups A and A is a chain COCR C(COOH)-O or a derivative thereofor a pair of groups A and A and each pair of groups A and A may be thesame or different and each pair forms the pairs of groups OM and H orCOJ; H and OC(D) CRCOOM; OCOCOR and H or COCI-I R (wherein J, R, R, Mand D have the values given above) or together form the chains COCRC(D)O, COCHRCI-I(D)O- or O-COCI-I CT (T being an alkyl or aryl group).

In order that the invention may be well understood, the followingexamples are given by way of illustration only, in which all parts aregiven by weight unless otherwise stated:

EXAMPLE 1 2,2'- Dicarboxy 6,6- bichromonyl monohydrate To a stirredsolution of sodium ethoxide in ethanol, prepared from 3.68 parts ofsodium and 50 parts of ethanol, was added a slurry of 2.7 parts of3,3-diacetyl-4,4'-dihydroxybiphenyl and 14.6 parts of diethyl oxalate in80 parts of diethyl ether. The mixture was stirred and heated undergentle reflux for 4 hours.

Water and diethyl ether were added followed by 10 parts of IO percentaqueous sodium hydroxide solution. The aqueous layer was separated andacidified with concentrated hydrochloric acid to give a pale greenprecipitate. This solid was crystallized from ethanol to give 1.0 partsof starting material as pale green needles, melting point 2156C.

The ethanol solution was then concentrated to a small volume from whichpale green needles crystallized. This solid was extracted with hotaqueous sodium bicarbonate solution. The solution was filtered, cooledand acidified with dilute hydrochloric acid to give a gelatinousprecipitate. This solid was filtered as well as possible andcrystallized, while still wet,

from ethanol to give 0.7 parts of 2,2 -dicarboxy-6,6 bicromonylmonohydrateas pale green needles, melting point 280C.

Analysis:

C I-I O H O requires:

EXAMPLE 2 2,2 -Dicarboxy-6,6 -bichromonyl monohydratea..4,4'-Bis(trans-1,2-dicarboxy vinyloxy)-biphenyl To a solution of 4.6parts of 4,4'-biphenol in parts of dioxan were added 1.15 parts ofmetallic sodium. The mixture was heated under reflux for 18 hours, and0.25 parts of unchanged sodium were removed. The mixture, under reflux,was treated with 10.3 parts of diethyl chlorofumarate and the resultingmixture was heated under reflux for 10 minutes. The mixture was cooledand acidified with 17 parts of 20% v/v aqueous sulphuric acid and heatedon a steam bath for 1 hour with 50 parts of 25 percent sodium hydroxidesolution. The mixture was cooled and acidified with 20 percent sulphuricacid, and the dioxan was distilled. The residue was diluted with 100parts of water and filtered. From the clear solution, on standing, therewas slowly deposited a solid, which was filtered off, washed with waterand dried to give 7.6 parts of 4,4'-bis-(trans-1,2-dicarboxy vinyloxy)-biphenyl monohydrate, melting point 260-70C. d.

Analysis:

Found C, 55.9; H, 3.67% C,.,H,,0,,,-H,0 requires: C, 55.6; H, 3.70%

b. 2,2Dicarboxy-6,6-bichromonyl monohydrate A mixture of 4 parts of4,4'-bis( transl ,2-dicarboxy vinyloxy)-biphenyl monohydrate and 18.5parts of concentrated sulphuric acid was stirred until it washomogeneous. The mixture was diluted with 80 parts of ice-water and theresulting insoluble material was filtered off, under gravity, and washedwith water. The wet solid was boiled with 70parts of ethanol and theinsoluble material was again filtered off under gravity. The materialwas then extracted with sodium bicarbonate solution and the extract wasre-acidified with dilute hydrochloric acid. The precipitated solid wasfiltered off and dried on a porous tile to give 0.25 parts of2,2-dicarboxy-6,6- bichromonyl monohydrate, melting point 280C, thestructure of which was confirmed by identity of the infra-red spectrumand mixed melting point with the material obtained by Example I.

EXAMPLE 3 2,2 -Dicarboxy-5,5 'dimethoxy-6,6-bichormonyl monohydrate a.Ethyl 6-iodo-5-methoxychromone-2-carboxylate To a stirred solution ofsodium ethoxide in ethanol, prepared from 3.54 parts of sodium and 60parts of ethanol, was added a slurry of 11.25 parts of3-iodo-6-hydroxy-2- methoxyacetophenone and l3 parts of diethyl oxalatein parts of diethyl ether. The mixture was stirred and heated undergentle reflux for 4 hours.

Water and diethyl ether were added and the aqueous layer separated. Theaqueous solution was acidified with dilute hydrochloric acid andextrated with ethyl acetate. The acetate solution was dried over sodiumsulphate and evaporated to leave a brown oil.

The oil was dissolved in boiling ethanol, 0.5 parts of concentratedhydrochloric acid were added and the solution was boiled for minutes. Ayellow solid which crystallized out on cooling, was shown to be amixture of acid and ester by thin layer chromatography.

This mixture was completely esterified by boiling with ethanolichydrogen chloride from which ll parts of the ester crystallized oncooling. This was recrystallized from an ethanol-dioxan mixture to give9.6 parts of ethyl 6-iodo-5- methoxychromone-2-carboxylate as yellowneedles, melting point 2024C.

Analysis:

C ii lo requires: I, 33.95%

b. 2,2'-Diethoxycarbonyl-5,5-dimethoxy-6,6-bichromonyl A mixture of 3.4parts of the ethyl 6-iodo-5-methoxychromone-2-carboxylate prepared asabove and 8 parts of copper bronze in 30 parts of dimethylformamide washeated at l55-60 for 6 hours. The hot solution was then filtered and thecopper was washed with hot dimcthylformamide.

The organic solution was poured into water and extracted continuouslywith hot ethyl acetate for hours. The ethyl acetate was concentrated tosmall volume to give a yellow crystalline solid. This solid wasrecrystallized from an ethanoldioxan mixture to give 0.34 parts of2,2'-diethoxycarbonyl-5 ,5 '-dimethoxy-6,6'-bichromonyl as pale yellowneedles, melting point 279-81C.

Analysis C ,,H O requires:

c. 2,2'-Dicarboxy-5,5'-dimethoxy-6,6'-bichromonyl monohydrate The freeacid was liberated from the above ester by treating a hot solution of0.26 parts of the 2,2-diethoxy-carbonyl-5,5- dimethoxy-6,6'-bichromonylin parts of ethanol and 5 parts of water with an'excess of sodiumbicarbonate. Water was added till all the sodium bicarbonate haddissolved and the heating was continued till thin layer chromotographyshowed complete hydrolysis of the diester.

The solution was then cooled and acidified with concentratedhydrochloric acid to give a yellow gelatinous precipitate. This solidwas filtered as well as possible and trimrated with ethanol. This solidwas collected by centrifugation and dried to give 0.13 parts of2,2'-dicarboxy-5,5-dimethoxy- 6,6-bichromonyl monohydrate as a yellowsolid, melting point 2756C.

Analysis:

Found: C, 58.1

, 3.27% c H o -H o requires: C, 3

d. 2,2-Dicarboxy-5,5' dimethoxy-,6'-bichromonyl disodium salt The freeacid was converted into its disodium salt by freeze drying a solution of0.12 parts of 2,2'-dica rboxy-5,5- dimethoxy-6,6-bichromonyl monohydrateand 0.044 parts of sodium bicarbonate in 40 parts of water to give 0.12parts of 2,2'-di-carboxy-5,5'-dimethoxy-6,6-bichromonyl disodium salt asa white solid.

EXAMPLE 4 Bis-( 7-benzyloxy-2-c arboxychromon-6-yl) sulphide monohydrateWater and diethyl ether were added, and the aqueous layer was collectedand acidified with dilute hydrochloric acid. The aqueous layer was thenextracted with ethyl acetate and, after drying over sodium sulphate, theethyl acetate was evaporated to leave a brown oil. This oil wasdissolved in boiling ethanol and 0.5 parts of concentrated hydrochloricacid were added. The solution was heated under reflux for 10 minutes.The solvent was removed under vacuum and the remaining oil washydrolized with hot sodium bicarbonate solution.

This solution was cooled and acidified with dilute hydrochloric acid togive 0.31 parts of bis-(7-benzyloxy-2-carboxychromon-6-yl) sulphidemonohydrate as a yellow solid, melting point 2646C.

Analysis:

Found: C H O S'H O requires:

C, 63.1; H, 3.94% C, 63.75; H, 3.75%

EXAMPLE 5 2,2-Dicarboxy-5 ,5 ,7' ,7 -tetramethoxy-8 ,8 '-bichromonylmonohydrate a. 2-Ethoxycarbonyl-8-iodo-5,7-dimethoxy chromone To astirred solution of sodium ethoxide, prepared from 4.6 parts of sodiumand parts of ethanol, was added a suspension of 9.8 parts of3-iodo-2-hydroxy-4,6-dimethoxyacetophenone in 18.3 parts of diethyloxalate and 100 parts of dioxan. The mixture was heated under reflux for4 hours, cooled, diluted with diethyl ether and extracted with water.The aqueous extracts were acidified with hydrochloric acid and extractedwith chloroform. After washing with water the chloroform extracts weredried and evaporated to leave a red solid which was dissolved in 100parts of boiling ethanol containing 3 parts of concentrated hydrochloricacid. Z-Ethoxycarbonyl-8-iodo-5,7-dimethoxy chromone was precipitated asa yellow powder on cooling, and was recrystallized from ethanol asyellow needles mp. 2089C.

Analysis:

Found: C H IO requires:

b. 2,2-Diethoxycarbonyl-5,5,7,7'-tetramethoxy-8,8- dichromonyl Anintimate mixture of 4 parts of the 2-ethoxycarbonyl- 8iodo-5,7-dimethoxy chromone and 18 parts of copper bronze was heated at220230C, for 4 hours, cooled and extracted with acetone. The acetoneextracts were charcoaled, filtered and evaporated to give a solid whichon recrystallization from ethyl acetate gave 2,2'-diethoxycarbonyl-5 ,5,7 ,7- tetramethoxy-8,8'-bichromonyl as yellow needles, mp. 2424C.

Analysis:

C, 60.5;H,4.71% C, 60.65; H, 4.73%

Found: C H O requires:

The structure was confirmed by mass spectroscopy.

c. 2,2'-Dica.rboxy-5,5,7,7'-tetramethoxy-8,8'-bichrornonyl monohydrateing was continued for 1 hour, followed by evaporation to remove ethanol,cooling and acidification with hydrochloric acid. The resulting solidcomprising 2,2-dicarboxy 5,5, 7,7- tetramethoxy-8,8'-bichromonylmonohydrate was filtered, washed with water, dried and recrystallizedfrom ethanol as yellow needles, m.p. 25860C.

0.17 parts of 2,2-dicarboxy-5,5, 7,7-tetramethoxy-8,8-

bichromonyl monohydrate was treated with 0.055 parts of sodium hydrogencarbonate in water. The resulting solution was filtered and freeze-driedto give the disodium salt of 2,2- dicarboxy-5,57,7'-tetramethoxy-8,8-bichromonyl.

EXAMPLE 6 a. 2,2-Dicarboxy-7,7-dimethoxy-8,8'-bichromonyl 2-Ethoxycarbonyl-8-iodo-7-hydroxychromone To a stirred suspension of 5.85parts of 2-ethoxylcarbonyl- 7-hydroxy chromone in 100 parts of ethanol,were added 2.54 parts of iodine and 0.88 parts of iodic acid dissolvedin parts of water. The mixture was stirred at room temperature for 4hours and the precipitated solid was filtered off. The solid comprising2-ethoxycarbony1-8-iodo-7-hydroxy chromone was crystallized from ethanolas a white solid, m.p. 218-9C.' The purity was determined by thin layerchromatography and the structure by nuclear magnetic resonancespectroscopy.

Analysis:

CMHBIOS requires:

b. 2-Ethoxycarbonyl-8-iodo-7-methoxy chromone A solution of 4.7 parts of2-ethoxycarbonyl-8-iodo-7- hydroxy chromone and 1.7 parts of dimethylsulphate in 50 parts of acetone was refluxed and stirred with 2 parts ofpotassium carbonate for 4 hours. The mixture was cooled and poured onto200 parts of water. The resulting solid comprising2-ethoxycarbonyl-87-methoxy chromone was filtered off, washed withwater, dried and crystallized from ethanol as a white solid, m.p.l54-5C.

Analysis:

Found: C, 41.2; H, 2.99%

C H lQ, requires: C, 41.7; H, 2.94%

c. 2,2'-Diethoxycarbonyl-7,7-dimethoxy-8,8-bichromonyl Analysis:

C, 62.7; H, 4.45% C, 63.15; H, 4.49%

Found: 26 2z m equires:

The purity was determined by thin layer chromatography and the structureby nuclear magnetic resonance and mass spectrometry.

d. 2,2'-Dicarboxy-7,7'-dimethoxy-8,8'-bichromonyl.

To a solution of 0.4 parts of 2,2-diethoxycarbonyl-7,7'-dimethoxy-8,8-bichromonyl in 25 parts of ethanol were added 0.2 parts ofsodium hydrogen carbonate. The mixture was heated to reflux temperatureand water added until in solution when refluxing was continued for 1hour. The solution was evaporated to remove ethanol, cooled andacidified with hydrochloric acid. The resulting solid comprising 2,2-dicarboxy-7,7-dimethoxy-8,8'-bichromonyl was filtered off, washed withwater, dried and crystallized from ethanol to give a yellow solid, m.p.2967C.

Analysis:

C, 59.6; H, 3.38% C, 60.28; H, 3.22%

. Found: 22 requires:

e. 2,2-Dicarboxy-7,7-dimethoxy-8,8-dichromonyl sodium salt The productwas converted into its disodium salt by treating 0.3 parts of2,2-dicarboxy-7,7-dimethoxy-8,8-bichromonyl with 0.12 parts of sodiumhydrogen carbonate in water. The

resulting solution was filtered and freeze-dried to give the disodiumsalt of 2,2'-dicarboxy-7,7-dimethoxy-8,8'-bichromonyl.

EXAMPLE 7 a. 2,2-Dicarboxy-6,6-dimethoxy-5,5"bichromonyl 2-Carboxy-6-hydroxychromone To a stirred solution of sodium ethoxideprepared from 8.75 parts of sodium and 140 parts of ethanol was added aslurry of 23 parts of 2-hydroxy-5-benzyloxy acetophenone and 25 parts ofdiethyl oxalate. After heating for 30 minutes the mixture was cooled,acidified with glacial acetic acid, diluted with 750 parts of water andextracted with chloroform. The chloroform extracts were dried andevaporated to give a solid which was heated under reflux with parts ofglacial acetic acid and 30 parts-of concentrated hydrochloric acid for12 hours. To the resulting cooled solution were added 300 parts of waterand the solid obtained was filtered off, dissolved in sodium bicarbonatesolution and acidified to give 12.1 parts of2-carboxy-6-hydroxy-chromone, m.p. 297-9C.

Analysis:

C, 57.75; ,H, 3.06% C, 58.26; H, 2.93%

Found: C H O requires:

b. 2-Ethoxycarbonyl-6-hydroxychromone c.2-Ethoxycarbonyl-S-iodo-6-hydroxychromone To a stirred warm solution of2.34 parts of the 2-ethoxycarbonyl--hydroxychromone in ethanol wereadded 1.01 parts of iodine and 0.35 parts of iodic acid dissolved in 5parts of water. After stirring for 5 hours at room temperature themixture was evaporated, the resulting solid collected, washed withsodium thiosulphate solution, dried and crystallized from ethanol togive 2 parts of 2-ethoxycarbonyl-5-iodo-6-hydroxychromone, m.p. lC asyellow needles.

Analysis:

Found: C, 40.8; H, 2.62; I, 35.4%

CWHBIOB requires: C, 40.0; H, 2.50; 1, 35.3%

The structure was confirmed by nuclear magnetic resonance spectroscopy.

d. 2-Ethoxycarbonyl-5-iodo-6-methoxychromone To a stirred solution ofthe 7.2 parts of 2-ethoxycarbonyl-5- iodo-6-hydroxychromone and 2.6parts of dimethyl sulphate in 50 parts of acetone were added 2.8 partsof potassium carbonate. The mixture was refluxed for 4 hours, cooled,poured into 200 parts of water, filtered and the resulting2-ethoxycarbonyl-5-iodo-6-methoxychromone (5.5 parts) was crystallizedfrom ethanol as yellow needles, m.p. 168-9C.

Analysis:

C H lO requires:

The structure was confirmed by nuclear magnetic resonance spectroscopy.

e. 2.2'-Diethoxycarbonyl-6,6-dimethoxy-5,5-bichromonyl To a solution of4 parts of the 2-ethoxycarbonyl-5-iodo6- methoxychromone in 35 parts ofdimethyl formamide were added parts of copper bronze. After heating for6 hours at l50l60C the mixture was cooled, filtered and diluted withwater. The resulting solid was filtered off, washed, dried andcrystallized from ethyl acetate to give 0.3 parts of 2,2-diethoxycarbonyl-6,6-dimethoxy-5,5-bichromonyl as yellow needles, m.p.243-4C Analysis:

Found: C, 63.6; H, 4.35%

C, .,H,2O, requires: C, 63.15; H, 4.49%

The structure was confirmed by mass and nuclear magnetic resonancespectroscopy.

f. 2,2-Dicarboxy-6,6'-dimethoxy 5,5-bichromonyl Analysis:

C, 60.6; H, 3.28% C, 60.2; H, 3.19%

Found: C H O, requires:

g. 2,2'-Dicarboxy-6,6 dimethoxy-5,5-bichromonyl disodium salt 0.2 partsof the 2,2'-dicarboxy-6,6'-dimethoxy-5,5- bichromonyl were treated with0.09 parts of sodium hydrogen carbonate in water. The resulting solutionwas freeze dried to give 0.2 parts of the disodium salt of 2,2-dicarboxy-6,6'- dimethoxy-S ,5 -bichromony1.

EXAMPLE 8 a. Bis-( 2-carboxy-5 -methoxychromon-8-yl) sulphide dihydrateTo a stirred solution of sodium ethoxide in ethanol, prepared from 1.84parts of sodium and 80 parts of ethanol, was added a slurry of 3.62parts of 3,3-diacety1-2,2- dihydroxy-4,4'-dimethoxydiphenyl sulphide and7.3 parts of diethyl oxalate in 80 parts of dioxan. The mixture wasstirred and heated under reflux for 16 hours.

Diethyl ether and water were then added and the aqueous layer wasseparated off and acidified with dilute hydrochloric acid. Theprecipitated oil was extracted with ethyl acetate and the organicsolution was dried over anhydrous sodium sulphate, filtered andevaporated. The residual oil was dissolved in boiling ethanol and 0.5parts of concentrated hydrochloric acid were added. The solution washeated under reflux for 15 minutes and was then allowed to cool.

The yellow solid which crystallized was filtered, dried and was thendissolved in a warm aqueous solution of sodium bicarbonate. The solutionwas treated with charcoal, filtered and acidified with dilutehydrochloric acid. The precipitated solid was filtered off, washed withwater and crystallized from dioxan to give 2.5 parts ofbis-(2-carboxy-5-methoxychromon-8-yl) sulphide dihydrate as a yellowsolid, melting point 270-2C.

Analysis:

Found: 22 u m '2H,O requires:

C,52.07; H,3.37; S,6.09% C,52.10; H,3.55; S,6.3l%

b. Bis-(2-carboxy-S-methoxychromon-8-y1)sulphide disodium salt Asolution of 0.592 parts of the bis-(2-carboxy-5-methoxychromon-8-yl)sulphide dihydrate and 0.197 parts of sodium bicarbonate in 35 parts ofwater was filtered and freeze dried to give 0.55 parts of bis-(2-carboxy-5-methoxychromon-8-y1) sulphide disodium salt as a yellowsolid.

EXAMPLE 9 a. Bis-( 2-carboxychromon-6-yl) sulphide monohydrate Themethod of Example 8 (a) was repeated using 1,14 parts of3,3'-diacetyl-4,4-dihydroxydiphenyl sulphide and 2.78 parts of diethyloxalate to give 0.7 parts of bis-(2-carboxychromon-6-yl) sulphidemonohydrate as a yellow solid, melting point 268-70C.

Analysis:

Found: C, 55.9; H, 3.14; S, 7.47% C .,H,,,0,,sH o requires: C, 56.0; H,2.8; S, 7.5%

b. Bis-(2-carboxychromon-6-yl) sulphide disodium salt A solution of0.521 parts of the 'bis-(2-carboxychromon-6 yl) sulphide monohydrate and0.205 parts of sodium bicarbonate in parts of water was filtered andfreeze-dried to give 0.500 parts of bis-(2-carboxychromon-6-yl) sulphidedisodium salt as a yellow solid.

EXAMPLE 10 a. Bis-(2-carboxy-7-methoxychromon-6-yl) sulphide monohydrateAnalysis:

Found: C H O SHJD requires:

b. Bis-(2-carboxy-7-methoxychromon-6-y1) sulphide disodium salt Asolution of 0.433 parts of the bis-(2-carboxy-7'methoxychromon-6-yl)sulphide monohydrate and 0.149 parts ofsodium bicarbonate in parts ofwater was filtered and freeze dried to give 0.42 parts ofbis-(2-carboxy-7-methoxychromon-fi-yl) sulphide disodium salt as ayellow solid.

EXAMPLE 1 l a. Bis-( Z-carboxy-7-methoxychromon-6-yl) sulphonemonohydrate To a suspension of 0.5 parts ofbis-(2-carboxy-7-methoxychromon-6-yl) sulphide monohydrate (produced asin Example 10 a) in 50 parts of glacial acetic acid were added 2.2 partsof 30% w/v hydrogen peroxide. The mixture was heated under reflux for 30minutes and was then allowed to cool. The solid which crystallized wasfiltered off and dried to give 0.45 parts of bis-(2-carboxy-'7-methoxychromon-6-yl) sulphone monohydrate as a white solid,melting point 283-5C.

Analysis:

Found:

- C, 50.43; H, 3.06; S, 5.84% C H O S-H O requires:

C, 50.8; H, 3.08; S, 6.16%

b. Bis-( 2-carboxy-7-methoxychromon-6-yl) sulphone disodium salt EXAMPLE1 2 a. 2,2-Dicarboxy-7,7'-bichromonyl sesquihydrate Ethyl-7-iodochromone-2-carboxylate To a stirred solution of sodium ethoxide inethanol, prepared from 1.5 parts of sodium in 30 parts of ethanol, wasadded a slurry of 4.25 parts of 2-hydroxy-4-iodoacetophenone and 5.9parts of diethyl oxalate in 30 parts of diethyl ether. The mixture wasstirred and heated under gentle reflux for 4 hours.

Water and diethyl ether were added and the aqueous layer was acidifiedwith concentrated hydrochloric acid. The solution was extracted withethyl acetate. The ethyl acetate solution was dried over sodiumsulphate, filtered and evaporated to leave a red oil.

This oil was dissolved in boiling ethanol containing 0.5 parts ofconcentrated hydrochloric acid and the solution was heated under refluxfor minutes. On cooling, a solid crystallized. This was washed withsodium bicarbonate solution. The insoluble solid was crystallized fromethanol to give 0.85 parts of ethyl 7-iodochromone-2-carboxylate,melting point 1456C, as pale yellow needles.

Analysis:

C I-1 10 requires:

The above sodium bicarbonate solution was acidified with dilutehydrochloric acid to give 2.75 parts of 7-iodochromone- 2-carboxylicacid, melting point 251-2C as a colorless solid.

Analysis:

C H lO, requires:

b 2,2'-Diethoxycarbonyl-7,7-bichromonyl Analysis:

C, 66.32; H, 4.17% C, 66,36; H, 4.18%

Found: C I-1 0 requires:

c. 2,2-Dicarboxy-7,7-bichromonyl sesquihydrate A solution of 0.5 partsof the 2,2-diethoxycarbonyl-7,7- bichromonyl in ethanol and water wastreated with an excess of sodium bicarbonate. The solution was heated inan open vessel till thin layer chromatography showed complete hydrolysisof the ester.

The solution was then cooled, treated with charcoal, filtered andacidified with concentrated hydrochloric acid to give a gelatinousprecipitate. The mixture was centrifuged and the supernatant liquid waspoured ofi'. The gel was triturated with hot ethanol to give 0.3 partsof 2,2-dicarboxy-7,7'-bichromonyl sesquihydrate, melting point 291-3C,as a colorless solid.

Analysis:

Found: zo m a' I 611 0 requires:

d. 2,2-Dicarboxy-7,7-bichromonyl disodium salt A solution of 0.24 partsof the 2,2'-dicarboxy-7,7'- bichromonyl sesquihydrate and 0.1 parts ofsodium bicarbonate in 40 parts of water. was freeze-dried to give 0.24parts of 2,2-dicarboxy-7,7-bichromonyl disodium salt as a pale yellowsolid.

EXAMPLE 13 a Bis-(2-carboxychromon-6 yl)ether sesquihydrate 4,4-Diacetoxydiphenyl ether.

Analysis:

. Found: C, 66.96; H, 4.82% C H Q, requires: C, 67.12; H, 4.93%

b. 3,3'-Diacetyl-4,4-dihydroxydiphenyl ether A mixture of 7.83 parts ofthe 4,4-diacetoxydipheny l ether,

4.16 parts of sodium chloride and 21.9 parts of aluminum chloride washeated to C and maintained at that temperature for 2 hours. Aftercooling, the resulting hard solid was broken up and decomposed by theaddition of 250 parts of water. The remaining solid was filtered off,suspended in boiling water for 5 minutes and filtered off again. Thesolid was crystallized from ethanol to give 6.1 1 parts of 3,3-diacetyl-4,4 '-dihydroxydiphenyl ether as a light brown solid, meltingpoint 181 C.

Analysis:

Found: 16 l4 5 equires:

c. Bis-( 2-carboxychromon-6-yl) ether sesquihydrate To a stirredsolution of sodium ethoxide in ethanol, prepared from 1.84 parts ofsodium and 30 parts of ethanol, were added 60 parts of diethyl etherfollowed by a slurry of 2.86 parts of the3,3'-diacetyl-4,4'-dihydroxydiphenyl ether and 7.3 parts of diethyloxalate in 30 parts of ethanol. The mixture was stirred and heated undergentle reflux for 4.5 hours.

Diethyl ether and water were then added and the aqueous layer wasseparated and acidified with dilute hydrochloric acid. The precipitatedoil was extracted with ethyl acetate and the organic solution was driedover anhydrous sodium sulphate, filtered and evaporated. The residualoil was dissolved in boiling ethanol and 0.5 parts of concentratedhydrochloric acid were added. The solution was heated under reflux for15 minutes and was then allowed to cool. The brown solid whichcrystallized was dissolved in an aqueous solution of sodium bicarbonateand the solution was heated on a steam bath for 2.5 hours. Aftercooling, the solution was filtered and acidified with dilutehydrochloric acid. The light brown precipitate was filtered off, washedwith water and dried to give 0.4 parts of bis-( 2-carboxychromon-6-yl)ether sesquihydrate, melting point 280lC.

Analysis:

Found: G l-1, 0,,- l sat-go requires:

d. Bis-( 2-carboxychromon-6-yl) ether disodium salt A solution of 0.55parts of the bis-( 2-carboxychromon-6-yl) ether sesquihydrate and 0.22parts of sodium bicarbonate in 150 parts of water was filtered andfreeze dried to give 0.5 parts of bis-( 2-carboxychromon-6-yl) etherdisodium salt as a buff solid.

EXAMPLE 14 a. Bis-( 2-carboxy-5-methoxychromon-8-yl) sulphonehemihydrate The method of Example 11 (a) was repeated usuing 0.9 partsof bis-( 2-carboxy-5 methoxychromon-8-yl) sulphide dihydrate (preparedas in Example 8 (a)) and 3.96 parts of 30% w/v hydrogen peroxide to give0.5 parts of bis-( 2-carboxy-5-methoxychromon-8-yl) sulphone hemihydrateas a white solid, melting point 2803C.

Analysis;

Found: C H O S' /QH O requires:

b. Bis-( 2-carboxy-5-methoxychromon-8-yl) sulphone disodium salt Asolution of 0.4 parts of the bis-(Z-carboxy-S-methoxychromon-8-yl)sulphone hemihydrate and 0.134 parts of sodiumbicarbonate in 35 parts ofwater was filtered and freeze dried to give 0.38 parts ofbis-(Z-carboxy-S-methoxychromon-8-y1) sulphone disodium salt as a whitesolid.

EXAMPLE a. 6,6-Dibromo-2,2'-dicarboxy-8,8'-bichromonyl 5-Bromo-2-hydroxy-3-iodoacetophenone.

iodoacetophenone as pale yellow needles, melting point Analysis:

Found: C, 28.06; H, 1.85; I, 36.8% C,,l-l,,l3rl0 requires: C, 28.15; H,1.76;], 37.24%

b. Ethyl 6-bromo-8-iodochromone-Z-carboxylate To a stirred solution ofsodium ethoxide in dry ethanol, prepared from 4.13 parts of sodium and100 parts of dry ethanol, was added a slurry of 15.2 parts of the5-bromo-2- hydroxy-3-iodoacetophenone and 16.3 parts of diethyl oxalatein parts of dry ethanol. The mixture was stirred and heated under refluxfor 4 hours.

The mixture was poured into a separating funnel containing ethyl acetateand dilute hydrochloric acid. The ethyl acetate layer was dried oversodium sulphate, filtered and evaporated to leave a brown oil. This oilwas dissolved in boiling ethanol containing 0.5 parts of concentratedhydrochloric acid. The solution was boiled for 5 minutes and allowed tocool, whence a yellow solid crystallized. I

This solid was recrystallized from ethanol to give 12.7 parts of ethyl6-bromo-8-iodochromone-Z-carb'oxylate as buff colored needles, meltingpoint l 568C.

Found: C H BrlQ, requires:

c. 6,6-Dibromo-2,2'-diethoxycarbonyl-8,8-bichromonyl A I mixture of 3.44parts of the ethyl 6-bromo-8- iodochromone-Z-carboxylate and 8.0 partsof copper bronze in 30 parts of dimethylformamide was heated at l55-65Cfor 6 hours. The solid was filtered off and washed with 15 parts of hotdimethylformamide.

Water was added to the filtrate and the buff'precipitate was filteredoff. This solid was crystallized from ethyl acetate to give 0.3 parts of6,6-dibromo-2,2'-diethoxycarbonyl- 8,8- bichromonyl as pale yellowmicro-needles, melting point 2l7-220C.

Analysis:

Found: C, 48.3; H, 2.7% C H Br O requires: C, 48.65; H, 2.7%

d. 6,6-Dibromo-2,2'-dicarboxy-8,8'-bichromonyl A mixture of 0.48 partsof the 6,6'-dibromo-2,2-diethoxycarbonyl-8,8-bichromonyl and 0.5 partsof sodium bicarbonate in aqueous ethanol was heated till thin layerchromatography showed complete hydrolysis of the ester. The solution wasfiltered, cooled and acidified with dilute hydrochloric acid to give agelatinous precipitate. On warming the mixture, the gel broke up to givea more solid precipitate. This solid was filtered off and crystallizedfrom dioxan to give 0.25 parts of6,6'-dibromo-2,2-dicarboxy-8,8'-bichromonyl as a colorless solid,melting point 334-6C.

Analysis:

Found:

1 .72% C H,,Br O,, requires: 1 .497:

e. 6,6'-Dibromo-2,2'-dicarboxy-8,8'bichromonyl disodium salt A solutionof0. l 76 parts of the 6,6-dibromo-2,2'-dicarboxy-8,8-bichromonyl and0.056 parts of sodium bicarbonate in 50 parts of water was treated withcharcoal, filtered and freeze dried to give 0.17 parts of6,6'-dibromo-2,2'-dicarboxy-8 ,8 bichromonyl disodium salt as a paleyellow solid.

EXAMPLE 16 a. 2,2'-Bis-(2-carboxychromon-6yl) acetic acid dihydrate 2,2-Bis-( 4-methoxyphenyl) acetic acid methyl ester To a solution of 40partsof 2,2-bis-(4-hydroxyphenyl) acetic acid and 67 parts of dimethylsulphate in 900 parts of acetone were added parts of potassiumcarbonate. The mixture was heated at reflux temperature with stirringfor 12 hours. It was then cooled and poured into water.

Theresulting oil was extracted into ether, and the ethereal solution waswashed with water, dried over sodium sulphate and evaporated to give anoil. The oil, which solidified on cooling, was crystallized frommethanol to give 40 parts of 2,2-bis-(4-methoxyphenyl) acetic acidmethyl esteras white needles, melting point 65 C.

Analysis:

Found: C H Q, requires:

b. 2,2-bis-( 3-acetyl-4-hydroxyphenyl )acetic acid To a stirred solutionof 38 parts of the 2,2-bis-(4-methoxyphenyl) acetic acid methyl esterand 21.5 parts of acetyl chloride in 600 parts of carbon disulphide wereadded 78 parts of aluminum chloride at room temperature. The mixture wasrefluxed for 6 hours and cooled. The carbon disulphide was removed bydecantation and the residue was hydrolized with ice and hydrochloricacid and extracted with diethyl ether. The ethereal solution wasextracted with sodium hydroxide solution. The alkaline extracts wereacidified with hydrochloric acid and extracted with diethyl ether.

The ethereal extracts were washed with water, dried over sodiumsulphate, filtered and evaporated to give a semi-solid which wastriturated with benzene. The resulting solid was crystallized fromethanol to give 9 parts of 2,2-bis-( 3-acetyl-4- hydroxphenyl)aceticacid, m.p. 2 l 35C.

The structure was confirmed by nuclear magnetic resonance and massspectroscopy.

Analysis:

C, 65.24; H, 4.81% C, 65.85; H, 4.88%

Found: C H O requires:

0. Ethyl 2,2-bi's-(3-acetyl-4-hydroxyphenyl)acetate Analysis:

C, 67.71; H, 5.46% C, 67.4; H, 5.62%

Found: C- H O, requires:

d. Ethyl 2,2-bis-(2-ethoxy carbonylchromon-B-yl) acetate To a stirredsolution of sodium sodium ethoxide in ethanol prepared from 3.68 partsof sodium and 200 parts of ethanol, was added a solution of 7 parts ofethyl-2,2-bis(3-acetyl-4- hydroxyphenyl)acetate an 14.6 parts of diethyloxalate, in 150 parts of dioxan at room temperature. The mixture washeated at reflux temperature for hours, cooled andpoured into water.

The resulting solution was extracted with diethyl ether and separated.The aqueous phase was acidified with hydrochloric acid and extractedwith diethyl ether, The ethereal solution was washed with water, driedover sodium sulphate, filtered and evaporated to give an oil, which wasboiled with ethanol and 2 drops of concentrated hydrochloric acid. Thesolid, which precipitated on cooling, was filtered and crystallized fromethanol to give 3.2 parts of ethyl 2,2-bis (2-ethoxycarbonylchromon-oyl)acetate as a solid, m.p. l52-4C. Th structure was confirmed by massspectroscopy.

Analysis:

Found: C, 64.03; H, 4.54%

C H O requires: C, 64.60; H, 4.61%

e. 2,2-bis-(2-carboxychromon-6-yl) acetic acid dihydrate Analysis:

Found: 22 l2 l0 2 req uires:

f. 2,2-Bis-( 2-carboxychromon-6-yl) acetic acid trisodium salt 0.21parts of 2,2 bis-(2-carboxychromon-6-yl) acetic acid dihydrate weretreated with 0.113 parts of sodium hydrogen carbonate dissolved in 50parts of water. The resulting solution was filtered and freeze dried togive the trisodium salt of 2,2-bis-( 2-carboxychromon-6-yl) acetic acid.

EXAMPLE 17 a. Ethyl 2,2-bis-( 2-carboxychromon-6-yl) acetate to asolution of 1 part of ethyl 2,2-bis(2-ethoxycarbonylchromon-6-yl)acetate (prepared as in Example l6(d)) in ethanol were added 0.35 partsof sodium hydrogen carbonate. The mixture was boiled, and water wasadded until a clear solution was obtained, The solution was boiled for 1hour, evaporated to remove ethanol, cooled and acidified withhydrochloric acid. The resulting solid was filtered, washed with water,dried and crystallized three times from ethyl acetate to give 0.4 partsof ethyl 2,2-bis-( 2-carboxychromon-6 -yl) acetate as a solid, m.p. 27881C. The structure was confirmed by nuclear magnetic resonancespectroscopy.

Analysisi C, 61.83; H, 3.68% C, 62.07; H, 3.45%

Found: u m m requires:

b. Ethyl 2,2-bis (2-carboxychromon-6-yl) acetate disodium. salt 0.464parts of ethyl 2,2-bis-( 2-carboxychromon-6-yl) acetate were treatedwith 0.168 parts of sodium hydrogen carbonate dissolved in 50 parts ofwater. The resulting solution was filtered freeze dried to give thedisodium salt of ethyl 2 ,2bis-( 2-carboxychromon-6-yl) acetate.

EXAMPLE 1 8 a. 1,2-Bis-( 2-carboxychromon-6-yl )-2,2-dichloroethylene a.l,1-Bis-(3-acetyl-4-hydroxyphenyl)-2,2-dichloroethylene To a stirredsolution of 13.9 parts of 1,1bis-(p-methoxyphenyl)-2,2,2-trichloroethane and 6.28 parts of acetylchloride in 200 parts of carbon disulphide, were slowly added 21.8 partsof anhydrous aluminum chloride. The mixture was heated at refluxtemperature for 24 hours, cooled and the carbon disulphide was decanted.The residue was hydrolized with ice and hydrochloric acid, extractedwith diethyl etherand the ethereal solution was then extracted withsodium hydroxide solution. The alkaline extracts were acidified withhydrochloric acid, extracted with diethyl ether and the etherealextracts were washed with water, dried over sodium sulphate andevaporated to give a brown solid, which was continuously ex tracted withpetroleum ether (b.pt. 6080C) for 3 days using a Soxhlet apparatus.Evaporation of the petroleum ether solution gave a yellow solid,which'was crystallized from ethanol, to give 4.3 parts of 1,1bis-(3-acetyl-4-hydroxyphenyl)-2,2- dichloroethylene, m.p. l68-l 70C.The structure was confirmed by nuclear magnetic resonance and massspectroscopy and its purity was determined by thin layer chromatography.

Analysis:

Found: lt'l fl z q requires:

b. 1,l-Bis-(22-carboxychromon-6-yl)-2,2-dich1oroethylene To a stirredsolution of sodium ethoxide in ethanol prepared from 2.1 parts of sodiumand parts of ethanol was added a solution of 4.2 parts of l,l-bis-(3-acetyl-4-hydroxyphenyl)- 2,2-dichloroethylene and 8.75 parts ofdiethyl oxalate in 100 parts of dioxan at room temperature. The mixturewas heated at reflux temperature for 5 hours, cooled, poured into waterand extracted with diethyl ether. The aqueous phase was acidified withhydrochloric acid and extracted with diethyl ether. The ether extractswere washed with water, dried over sodium sulphate and evaporated togive a yellow oil, which was dissolved in ethanol and 2 drops ofconcentrated hydrochloric acid and boiled for 15 minutes. The ethanolwas then evaporated off and the resulting oil was redissolved in ethanoland treated with an excess of sodium hydrogen carbonate. The mixture wasboiled and water was added until a clear solution was obtained. Afterboiling the solution for 30 minutes, the ethanol was evaporated off andthe aqueous solution was acidified with hydrochloric acid. The resultingsolid was filtered off, washed with water, dried and crystallized twicefrom ethanol to give 1.1 parts of l,1-bis(2-ca.rboxychromon-6-yl)-2,2-dichloroethylene as a white solid, m.p.3045C. The structure was confirmed by nuclear magnetic resonancespectroscopy.

Analysis:

Found: C, 56.42; H, 2.25%

C H, Cl,O,, requires: C, 55.81; H, 2.11%

c. l ,1-Bis-(2-carboxychromon-6-yl)-2,2-dichloroethylene disodium saltEXAMPLE 19 a. Bis-( 2-carboxychromon6-yl) methane Bis-( 3-acetyl-4-hydroxyphenyl) methane A mixture of 14.2 parts of bis-(4-acetoxyphenyl)methane, 21.7 parts of aluminum chloride and 9 parts of sodium chloridewas heated for 4 hours at 140l50C. After cooling the mixture washydrolized with ice and hydrochloric acid and extracted with ethylacetate. The ethyl acetate solution was extracted with dilute sodiumhydroxide solution which was then acidified with hydrochloric acid andextracted with ethyl acetate. The ethyl acetate solution was washed withwater, dried over sodium sulphate and evaporated to give a solid whichwas crystallized from ethanol and recrystallized from dioxan to yield 4-parts of bis-(3-acetyl-4-hydroxyphenyl) methane as a white solid, m.p.l567C. The purity was checked by thin layer chromatography and thestructure by nuclear magnetic resonance spectroscopy.

Analysis:

Found: 72.4; H, 5.94%

To a stirred solution of sodium ethoxide in ethanol prepared from 0.65parts of sodium and 20 parts of ethanol was added a solution of 1.9parts of bis-(3-acetyl-4-hydroxy-phenyl) methane and 1.8 parts ofdiethyl oxalate in 50 parts of dioxan. The mixture was stirred at roomtemperature for 30 minutes and at reflux temperature for 24 hours.

After cooling, the solution was poured into water and extracted withdiethyl ether. The aqueous extracts were acidified with concentratedhydrochloric acid and extracted with diethyl ether. The etherealsolution was washed with water, dried over sodium sulphate andevaporated to yield an oil which was refluxed for 10 minutes in ethanolwith 2 drops of concentrated hydrochloric acid. Bis-(2-ethoxycarbonylchromon-6-yl) methane hydrate was precipitated oncooling and this was recrystallized from ethanol to give 0.8 parts of awhite solid, mp. l835C. The structure was confirmed by massspectroscopy.

Analysis:

C, 64.5; H, 4.50% C, 64.4; H, 4.72%

Found 2s z00,,' O requires:

0. Bis-( 2-carboxychromon-6-yl) methane hydrochloric acid. Theprecipitate was filtered off, washed with water; dried and crystallizedfrom ethanol to give 0.2 parts of bis-(Z-carboxychromon--yl) methane asa while solid, m.p. 2956C.

Analysis:

C l-l o requires:

Found: C, 63.8; H, 3.21%

d. Bis-(2-carboxychromon-6-yl)methane disodium salt 0.2 parts ofbis-(2-carboxychromon-6-yl) methane were treated with 0.084 parts ofsodium hydrogen carbonate in water. The resulting solution was filteredand freeze dried to give the disodium salt of bis-(2-carboxychromon-6-ylmethane.

EXAMPLE 20 a. Bis-( 2-carboxychromon-6-yl)pyrid-2 yl methane hydrateBis-( 3-acetyl-4-hydroxyphenyl) pyrid-2-yl methane An intimate mixtureconsisting of 7.2 parts of bis-(4-acetoxyphenyl) pyrid-2-yl methane,16.7 parts of aluminum chloride and 3.5 parts of sodium chloride washeated at l45l60C. for 3 hours. After cooling, the mixture washydrolized with ice and hydrochloric acid and extracted with diethylether.

The aqueous phase was neutralized with sodium bicarbonate solution andextracted with diethyl ether. The ethereal extracts were washed withwater, dried over sodium sulphate and evaporated to give an oil. Thesolid which formed when the oil was triturated with cold petroleumspirit (boiling range 4060C) was crystallized twice from petroleumspirit (boiling range 6080C) to give 3 parts of bis-(3-acetyl-4hydroxyphenyl) pyrid-2-yl methane, m.p. l l0-l 13C.

Analysis:

Found C, 35

To a stirred solution of sodium ethoxide prepared from 1 part of sodiumand 20 parts of ethanol, was added a solution of 4 parts of bis-(3-acetyl-4-hydroxyphenyl) pyrid-2-yl methane and 3.2 parts of diethyloxalate in parts of dioxan.

The mixture was refluxed for 4 hours,cooled, poured into water andextracted with diethyl ether. The aqueous phasewas then neutralized withdilute hydrochloric acid and extracted with diethyl ether. The etherealsolution was washed with water, dried over sodium sulphate andevaporated to give an oil, which was boiled for 5 minutes with 50 partsof ethanol containing 2 parts of concentrated hydrochloric acid.

The solution was cooled, diluted with water and basified with sodiumbicarbonate solution. The resulting solid was filtered, washed, driedand crystallized from ethanol to give 2 parts of bis-(2-ethoxycarbonylchromon-6yl) pyrid-2-yl methane, m.p. l7l-3C. The puritywas confirmed by thin layer chromatography and the structure by massspectrometry. I

c. Bis-( 2-carboxychromon-6-yl) pyrid-Z-yl methane hydrate Analysis:

Found: C ,,H,,,NO,,'H O requires:

d. Bis-( 2-carboxychromon-6yl) pyrid-Z-ylmethane disodium salt 7 0.243parts of bis-( 2-carboxychromon-6-yl) pyrid-2-yl methane hydrate weretreated with 0.084 parts of sodium hydrogen carbonate dissolved in 50parts of water. The resulting solution was filtered and freeze dried togive the disodium salt of bis-( 2-carboxychromon-6-yl) pyrid-2-ylmethane.

EXAMPLE 21 Bis- [2-carboxy-7-( Z-hydroxypropoxy) chromon-8-yl] methanedisodium salt a. Bis- [3-acetyl-2-hydroxy-6-(2-hydroxypropoxy) phenyl]methane Analysis:

C, 63.2; H, 6.3% C, 63.9; H, 6.5%

Found: C I-1 requires:

b. Bis- 2-ethoxycarbonyl-7-( 2-hydroxy propoxy )chromon-8- yl] methane Asolution of 1.6 parts bis[3-acetyl-2-hydroxy-6 (Z-hydroxypropoxy)phenyl] methane and 3.5 parts of diethyl oxalate in 30 parts by volumeof ethanol was added to a solution of 0.9 parts of sodium in 30 parts byvolume of ethanol. The yellow mixture was refluxed for 4 hours. Thesolution was poured into 300 parts by volume of ether and the productswere extracted with water. A solid, insoluble in water and ether, wasfiltered off. This solid was boiled with about parts of ethanolcontaining 0.5 parts -of hydrochloric acid for 10 minutes. The filteredsolution gave, on cooling, 0.2 parts of bis-[2-ethoxycarbonyl-7-(2-hydroxypropoxy)chromon-8-yl] methane, m.p. l924C.

The original aqueous extracts were acidified and the products wereextracted into chloroform. The dried chloroform extracts, onevaporation, gave a yellow oil/This was boiled with 10 parts by volumeof ethanol containing 0.5 parts of hydrochloric acid for 10 minutes. Theethanolic solution on evaporation gave 0.7 parts of crude chromoneester. This solid in chloroform was washed with sodium bicarbonatesolution. The dried chloroform extracts on evaporation gave 0.5 parts ofpure chromone ester, m.p. l946C raised to l978C (from ethanol).

Analysis:

C, 62.62; H, 5.2% C, 62.38; H, 5.4%

Found: ar u requires;

c. Bis- {2-carboxy-7-( 2-hydroxypropoxy)chromon-8-yl] methane disodiumsalt EXAMPLE 22 2,2-Bis-(2-carboxychromon-6-yl) propane disodium salt Toa stirred solution of sodium ethoxide, prepared from 2.3 parts of sodiumand parts of ethanol, were added 11.4 parts of 2,2-bis-(p-hydroxyphenyl)propane. The solution was then evaporated leaving the sodium salt of thephenol as a white solid. This was suspended in 250 parts of refluxingdry dioxan and to it were added 20.65 parts of diethyl chlorofumarate.Refluxing was continued for 1 hour, the mixture was kept at roomtemperature for 18 hours, and the dioxan was evaporated to give an oil.The oil was refluxed with 100 parts of 10 percent sodium hydroxidesolution and 20 parts of ethanol for 1 hour, cooled, and extracted withether. The aqueous layer was saturated with carbon dioxide and nonacidicmaterial was extracted with ether. The aqueous layer was then acidifiedto give an oil which was triturated with 100 parts of cold concentratedsulphuric acid for 1 hour. The viscous red solution was poured intocrushed ice to give an oily gum which was washed by decantation and thenextracted with a warm solution of sodium hydrogen carbonate. Thissolution precipitated colorless plates on cooling, which wererecrystallized from water to give 0.65 parts of2,2-bis-(2-carboxychromon--yl) propane disodium salt tetrahydrate, ascolorless plates.

Analysis:

' Found: C l-L O Na -4H O requires:

EXAMPLE 23 a. Bis-(2-ethoxycarbonylchromon-6-yl) ketone An intimatemixture of 5 parts of 4,4'-diacetoxybenzophenone and 20 parts ofanhydrous aluminum chloride was heated to l70-l80 C. over a period of 20minutes, and maintained at that temperature for a further 45 minutes.The cooled product was hydrolized with 100 parts of water containing 5parts of concentrated hydrochloric acid.

The precipitated solid was filtered off, washed with 3 X 50 parts ofwater, and recrystallized from a boiling mixture of parts of ethanol and40 parts of acetone to give 3.1 parts of3,3'-diacetyl-4,4-dihydroxybenzophenone as a grey solid, m.p. l74-l76C.

To a stirred suspension of 3 parts of 3,3-diacetyl-4,4-dihydroxybenzophenone in 15 parts of diethyl oxalate, 30 parts of ethylalcohol and 15 parts of ether, was added a solution of 1.5 parts ofsodium in 20 parts of ethyl alcohol. The mixture was stirred and heatedunder reflux for 2 hours.

Five-hundred parts of ether were then added, and the precipitated solidwas filtered off, washed with 2 X 100 parts of ether, and dried. Thissolid was dissolved in 250 parts of water, and the acidified solutionwas extracted twicewith 100 parts of chloroform. The combined extractswere dried over sodium sulphate, and evaporated to dryness to leave abrown oil.

This oil was dissolved in 10 parts of boiling ethyl alcohol, and 0.1parts of concentrated hydrochloric acid were added. The mixture washeated under reflux for 30 minutes to give 1.9 parts of bis-(Z-ethoxycarbonylchromon-6-yl) ketone as a white solid, m.p. 2l820C.

Analysis:

Found: zs O requires:

b. Bis-( 2-carboxychromon-6-yl) ketone disodium salt To a refluxingsuspension of 0.302 parts of bis-(2-ethoxycarbonylchromon-6-yl) ketonein 5 parts of ethyl alcohol and 5 parts of water was added a solution of0.0523 parts of sodium hydroxide in 1.3 parts of water. The mixture wasstirred and heated under reflux for 30 minutes and then parts of ethanolwere added. The precipitated solid was isolated, dissolved in water,charcoaled, and reprecipitated with an equal volume of ethyl alcohol togive 0.1 parts of bis( 2-carboxychromon-6-yl) ketone, disodium salt,dihydrate, as a pale yellow solid.

Analysis:

Found: C,,H, Na,-2H,O requires:

EXAMPLE 24 10 Bis-( 2-carboxy-7-methoxychromony-8-yl) methanesesquihydrate a. Bis-( 3-acetyl-2-hydroxy-6-methoxyphenyl) methane Amixture of 1 part of bis-( 3-acetyl-2, 6-dihydroxyphenyl) methane, 8parts of methyl iodide and 2 parts of powdered potassium carbonate washeated under reflux in parts by volume of acetone for 16 hours. Theacetone solution was evaporated and water was added to the solidresidue. The crude insoluble product was filtered off and washed withether to give 0.8 parts of bis-( 3-acetyl-2-hydroxy-6-methoxyphenyl)methane, m.p. 247-9C after crystallization from acetone.

Analysis: 25

Found: C H O requires:

b. Bis-( 2-carboxy-7-methoxychromon-8-yl) methane and Bis-(2-ethoxycarbonyl 7-methoxychromon-8-yl) methane A solution of 1.5 partsof bis-( 3-acetyl-2-hydroxy-6- methoxy-phenyl) methane in 4 parts ofdiethyl oxalate was added to a solution of 1 part of sodium in 30 partsby volume of ethanol. The yellow mixture was refluxed for 4 hours. Itwas 5 then poured into 300 parts by volume of ether and the product wasextracted with water (A). Some of the product, insoluble in water, wasfiltered off. This solid was boiled with about 10 parts of ethanolcontaining a catalytic amount of hydrochloric acid for 10 minutes. Thefiltered solution on cooling gave a white solid which was found to bemainly bis-(2-ethoxycarbonyl-7-methoxy-chromon-8-yl) methane togetherwith some of the corresponding bis-chromone acid. The solid wasdissolved in chloroform and this solution was washed with sodiumbicarbonate solution. The dried chloroform extracts on evaporation gave0.1 parts of bis-(2-ethoxycarbonyl-7- methoxychromon-S-yl) methane, m.p.225-226C.

Analysis:

Found:

C H O requires:

Analysis:

C, 57.7; H, 4.3% C, 57.6; H, 4.0%

Found: C l-1, 0 1 map requires:

This acid was dissolved in water containing an equivalent amount ofsodium bicarbonate and freeze dried to obtain the disodium salt.

EXAMPLE 25 Di-( 2-carboxychromon-6-yl )amine a.N-Acetyl-3,3'-diacetyl-4,4-dihydroxydiphenylamine An intimate mixture of6.2 parts of N-acetyl-4,4'-diacetoxydiphenylamine and 15.6 parts ofaluminum chloride was heated at 180-5C for 3 hours. The melt was cooledand melting point l989C.

Found: C H NO requires:

b. Di( 2-carboxychromon-6-yl )amine dihydrate To a stirred solution of2.07 parts of sodium in 50 parts of dry ethanol was added a slurry of3.27 parts of Nacetyl-3,3- diacetyl-4,4-dihydroxydiphenylamine and 8.0parts of diethyl oxalate in 50 parts of dry ethanol. The mixture wasstirred and refluxed for 4 hours.

The mixture was cooled and poured into a separating funnel containingethyl acetate and dilute hydrochloric acid. The ethyl acetate layer wasseparated and evaporated to dryness to leave a brown oil. This oil wasdissolved in ethanol containing 1.0 parts of concentrated hydrochloricacid and the solution was refluxed for 20 minutes.

The solvent was evaporated to leave a red oil which was hydrolyzed withsodium bicarbonate in aqueous ethanol. When hydrolysis was complete thesolution was cooled and acidified with dilute hydrochloric acid to givea brown sticky precipitate.

The supernatant liquid was poured off and the precipitate was boiledwith ethanol to leave di(2-carboxychromon-6- yl)amine dihydrate as areddish brown solid, melting point 3035C(d). More of this materialcrystallized from the ethanol washings to give a total yield of 0. 1 5parts.

Analysis: Found: C H NO QH O requires:

c. Di-(2-carboxychromon-6-yl)amine disodium salt A solution of 0.122parts of di-( 2-carboxychromon-6-yl) amine dihydrate and 0.048 parts ofsodium bicarbonate of 30 parts of water was freeze-dried to give 0.12parts of di-(2-carboxychromon-6-yl) amine disodium salt as a yellowsolid.

EXAMPLE 26 I 2,2'-Dicarbox,y-8,8-bichromonyl a. o-lodophenoxyfumaricacid To a solution of 11 parts of o-iodophenol and 7.6 parts of dimethylacetylenedicarboxylate in 100 parts of dry dioxan v was added 1 part ofbenzyl trimethylammonium hydroxide. The solution was heated at 100C for40 minutes, cooled, basified with 35 parts of 25 percent sodiumhydroxide solution and heated for 2 hours at 100C.

The mixture was then cooled, washed with diethyl ether, acidified withconcentrated hydrochloric acid and extracted three times with 75 partsof diethyl ether.

The ethereal extracts were washed with water, dried over sodium sulphateand evaporated to give a pale yellow solid.

The solid was crystallized from water to give 13.5 parts ofoiodophenoxyfumaric acid m.p. 1847C.

Analysis:

Found C, 36.0, H, 2 10; 1, 38.9% C l-LlO requires: C, 35.9, H, 2 10; 1,38.0%

b. 2-Carboxy-8 iodo chrornone A solution of 8 parts ofo-iodophenoxyfumaric acid in 40 parts of concentrated sulphuric acid wasallowed to stand at room-temperature for 5 minutes. The solution wasthen poured on to ice to give a solid which was filtered off, washedwith water, dried and crystallized from ethanol to give 3.3 parts of2-carboxy-8-iodo chromone m.p. 277C(d).

2. A compound according to claim 1, wherein X is a carbon-carbon bond; asulphur or oxygen atom, or a group -CH2-, -CHOH-, -C(R4)2-, -CO-,-CH(COOH)-, -CH(COOR4)-, , -NH-, -SO- or -SO2-, and R4 represents alower alkyl group.
 3. A compound according to claim 1, wherein both R1groups are hydrogen.
 4. A compound according to claim 1, wherein X is acarbon -carbon bond or an -NH- group, which bond or group links the6,6'' positions of the chromone nuclei.
 5. A compound according to claim1, wherein -X- links the same positions on each chromone nucleus and isa carbon - carbon bond, a sulphur or oxygen atom, or a group -SO2-,-CH(COOH)-, -CH(COOC2H5)-, , -CH2-,
 6. A compound according to claim 1in the form of a pharmaceutically acceptable salt thereof.
 7. A compoundaccording to claim 6 wherein the salt is selected from salts having analkaline earth, alkali-metal, piperidinium, pyridinium or mono- di- ortri-lower alkyl or lower alkanol ammonium cation, or the ammoniumcation.
 8. A compound according to claim 7, wherein the salt is thesodium salt.
 9. A compound according to claim 5 in the form of apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 1 which is 2,2''-dicarboxy 6, 6''-bichromonyl.
 11. A compoundaccording to claim 1 which is 2,2''-dicarboxy-5,5''-dimethoxy-6,6''-bichromonyl.
 12. A compound according to claim 1which is bis-(7-benzyloxy-2-carboxychromon-6-yl)sUlphide.
 13. A compoundaccording to claim 1 which is 2,2''-dicarboxy-5, 5'',7,7''-tetramethoxy-8,8''-bichromonyl.
 14. A compound according to claim1 which is 2,2''-dicarboxy-7, 7''-dimethoxy-8,8''-bichromonyl.
 15. Acompound according to claim 1 which is 2,2''-dicarboxy-6,6''-dimethoxy-5,5''-bichromonyl..
 16. A compound according to claim 1which is bis-(2-carboxy-5-methoxychromon-8-yl)sulphide.
 17. A compoundaccording to claim 1 which is bis-(2-carboxychromon-6-yl)sulphide.
 18. Acompound according to claim 1 which isbis-(2-carboxy-7-methoxychromon-6-yl)sulphide.
 19. A compound accordingto claim 1 which is bis-(2-carboxy-7-methoxychromon-6-yl)sulphone.
 20. Acompound according to claim 1 which is 2,2''-dicarboxy-7,7''-bichromonyl.
 21. A compound according to claim 1 which isbis-(2-carboxychromon-6-yl)ether.
 22. A compound according to claim 1which is bis-(2-carboxy-5-methoxychromon-8-yl)sulphone.
 23. A compoundaccording to claim 1 which is6,6''-dibromo-2,2''-dicarboxy-8,8''-bichromonyl.
 24. A compoundaccording to claim 1 which is 2,2''-bis-(2-carbocychromon-6-yl) aceticacid.
 25. A compound according to claim 1 which is ethyl2,2''-bis-(2-carboxychromon-6-yl)acetate.
 26. A compound according toclaim 1 which is 1,1''-bis-(2-carboxychromon-6-yl)-2,2-dichloroethylene.27. A compound according to claim 1 which is bis-(2-carboxychromon-6-yl)pyrid-2-yl methane.
 28. A compound according to claim 1 which isbis-(2-carboxychromon-6-yl) methane.
 29. A compound according to claim 1which is bis-(2-carboxy-7-(2-hydroxypropoxy)chromon-8-yl) methane.
 30. Acompound according to claim 1 which is 2,2''-bis-(2-carboxychromon-6-yl)propane.
 31. A compound according to claim 1 which isbis-(2-carboxychromon-6-yl) ketone.
 32. A compound according to claim 1which is bis-(2-carboxychromon-8-yl) methane.
 33. A compound accordingto claim 1 which is di-(2-carboxychromon-6-yl) amine.
 34. A compoundaccording to claim 1 which is 2,2''-dicarboxy-8, 8''-bichromonyl.